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Ma Z, Zhang Y, Sun D, Zhu M, Yi J, Zhang Y, An Z, Zhang Y. Thromboembolic and bleeding events associated with angiogenesis inhibitors in cancer patients. Expert Opin Drug Saf 2025:1-10. [PMID: 40246589 DOI: 10.1080/14740338.2025.2494688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 02/19/2025] [Accepted: 03/05/2025] [Indexed: 04/19/2025]
Abstract
BACKGROUND Angiogenesis inhibitors are associated with increased risk of thromboembolic events (TEEs) and hemorrhagic events. However, their clinical features are not well characterized in real-world studies. RESEARCH DESIGN AND METHODS First, we conducted a pharmacovigilance study to investigate characteristics of TEEs and bleeding and compare vascular endothelial growth factor and its receptor inhibitors (VEGF/VEGFRIs) with other antiangiogenic agents. Second, we performed a retrospective analysis of lung cancer patients who received bevacizumab or anlotinib to assess the incidence of VEGF/VEGFRI-associated TEEs and bleeding. RESULTS In the pharmacovigilance study, both VEGF/VEGFR-targeted biologics and VEGFR-tyrosine kinase inhibitors were associated with higher reporting of arterial thromboembolism (ATE) (reporting odd ratio (ROR) 2.91; ROR 1.25; respectively), and bleeding (ROR 2.56; ROR 2.35; respectively). Venous thromboembolism (VTE) was only associated with VEGF/VEGFR-targeted biologics (ROR 3.11). In the cohort study, bevacizumab, aflibercept, and ramucirumab showed the strongest associations with VTE, ATE, and bleeding, respectively. In the cohort study of 261 lung cancer patients treated with bevacizumab or anlotinib, 42.9% were older than 65 years, 62.1% were male, with TEEs occurred in 11.5%, and bleeding in 8.8%. CONCLUSIONS All VEGF/VEGFRIs were associated with increased ATE and bleeding risk. VEGF/VEGFR-targeted biologics also significantly raise the risk of VTE.
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Affiliation(s)
- Zhuo Ma
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Yi Zhang
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Dan Sun
- Department of Respiratory and Critical Care Medicine, Civil Aviation Medicine Center of CAAC (Civil Aviation General Hospital), Beijing, China
| | - Min Zhu
- Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Jiawen Yi
- Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Yixiao Zhang
- Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Zhuoling An
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Yuhui Zhang
- Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
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2
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Garemilla SSS, Gampa SC, Garimella S. Role of the tumor microenvironment in cancer therapy: unveiling new targets to overcome drug resistance. Med Oncol 2025; 42:202. [PMID: 40332723 DOI: 10.1007/s12032-025-02754-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 04/28/2025] [Indexed: 05/08/2025]
Abstract
Cancer is a leading cause of death globally, with resistance to therapy representing a major obstacle to effective treatment. The tumor microenvironment (TME), comprising a complex network to cellular and non-cellular components including cancer-associated fibroblasts, immune cells, the extracellular matrix and region of hypoxia, is integral to cancer progression and therapeutic resistance. This review delves into the multifaceted interactions within the TME that contribute to tumor growth, survival and immune evasion. Key elements such as the role of cancer- associated fibroblasts in remodeling the extracellular matrix and promoting angiogenesis, the influence of immune cells such as tumor-associated macrophages in creating an immunosuppressive milieu and the impact of hypoxia conditions on metabolic adaptation and therapy resistance are thoroughly examined. This review evaluates current and emerging TME-targeted therapeutic strategies, including inhibitors of extracellular matrix components, modulators of immune cell activity and approached to alleviate hypoxia. Combination therapies that integrate TME-targeted agents with conventional treatments such as chemotherapy and immunotherapy are also discussed for their potential to enhance treatment efficacy and circumvent resistance mechanisms. By synthesising recent advances in TME research and therapeutic innovation, this paper aims to underscore the importance of TME in cancer therapy and highlight promising avenues for improving patient outcomes through targeted intervention.
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Affiliation(s)
| | - Siri Chandana Gampa
- Department of Life Sciences, GITAM (Deemed to be University), Visakhapatnam, Andhra Pradesh, 530045, India
| | - Sireesha Garimella
- Department of Life Sciences, GITAM (Deemed to be University), Visakhapatnam, Andhra Pradesh, 530045, India.
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3
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Lorenc P, Dams-Kozlowska H, Guzniczak N, Florczak-Substyk A. Application of nanoparticles to target tumor blood vessels as a promising cancer treatment strategy. Biomed Pharmacother 2025; 186:118038. [PMID: 40215646 DOI: 10.1016/j.biopha.2025.118038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 03/31/2025] [Accepted: 04/03/2025] [Indexed: 04/25/2025] Open
Abstract
Cancer remains one of the leading causes of death worldwide and poses a significant challenge to effective treatment due to its complexity. Angiogenesis, the formation of new blood vessels, is a critical process in tumor growth and metastasis. The VEGF/VEGFR pathway plays a crucial role in regulating angiogenesis. Many anti-angiogenesis agents, including monoclonal antibodies and tyrosine kinase inhibitors, have been investigated for the treatment of various cancers. However, they face significant limitations such as limited bioavailability and drug resistance. Nanoparticles have emerged as a promising tool for effective drug delivery while minimizing systemic side effects. This review explores the application of nanoparticles dedicated to angiogenesis-targeted cancer therapy, particularly targeting the VEGF/VEGFR pathway. We describe drug delivery systems based on inorganic, lipid, and polymeric nanoparticles. Moreover, special attention is given to functionalized nanoparticles, which can precisely target numerous proteins that are significantly overexpressed on the surfaces of endothelial cells, tumors, or other cells in the tumor microenvironment. We summarize a series of nanoparticles designed for selective targeting of tumor vasculature, emphasizing the challenges faced by anti-angiogenic cancer therapies.
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Affiliation(s)
- Patryk Lorenc
- Chair of Medical Biotechnology, Department of Cancer Immunology, Poznan University of Medical Sciences, 8 Rokietnicka St, Poznan 60-806, Poland; Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary St, Poznan 61-866, Poland; Doctoral School, Poznan University of Medical Sciences, 70 Bukowska St, Poznan 60-812, Poland
| | - Hanna Dams-Kozlowska
- Chair of Medical Biotechnology, Department of Cancer Immunology, Poznan University of Medical Sciences, 8 Rokietnicka St, Poznan 60-806, Poland; Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary St, Poznan 61-866, Poland
| | - Natalia Guzniczak
- Chair of Medical Biotechnology, Department of Cancer Immunology, Poznan University of Medical Sciences, 8 Rokietnicka St, Poznan 60-806, Poland
| | - Anna Florczak-Substyk
- Chair of Medical Biotechnology, Department of Cancer Immunology, Poznan University of Medical Sciences, 8 Rokietnicka St, Poznan 60-806, Poland; Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary St, Poznan 61-866, Poland.
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Aghasizadeh M, Moghaddam T, Bahrami AR, Sadeghian H, Alavi SJ, Kazemi T, Matin MM. Evaluation of several farnesyloxycarbostyril derivatives as potential 15-LOX-1 inhibitors for prostate cancer treatment. Toxicol Appl Pharmacol 2025; 498:117293. [PMID: 40057000 DOI: 10.1016/j.taap.2025.117293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 02/20/2025] [Accepted: 03/04/2025] [Indexed: 03/15/2025]
Abstract
The impact of 15-lipoxygenase-1 (15-LOX-1) in the progression of prostate cancer (PCa) is noteworthy, as it correlates with the Gleason score of the disease. Thus, development of specific 15-LOX-1 inhibitors would be desirable for targeted therapy of PCa. This study focused on evaluating the anti-prostate cancer potency of three farnesyloxycarbostyril derivatives, 6-, 7- and 8-farnesyloxycarbostyril (6-, 7- and 8-FQ), as potential inhibitors of 15-LOX-1 on PCa cells. To this end, the enzymatic activity of 15-LOX was first assessed in PCa and human dermal fibroblast (HDF) cells. Subsequently, the cytotoxic effects and apoptosis-inducing capabilities of the compounds were assessed through MTT assay and FITC-annexin V/PI staining, respectively. Among the compounds, 8-FQ was selected for further assessment in a mouse model bearing xenograft human PCa tumor. The results demonstrated that the most effective compound, 8-FQ, caused an 84-fold and 15.7-fold reduction in 15-LOX activity in PC-3 cells at 30 and 14 μM concentrations, respectively. The MTT assay revealed a dose- and time-dependent toxicity of the compounds on PCa cells, and flow cytometry results indicated that apoptosis served as the dominant mechanism of cell death. Given the upregulation of 15-LOX-1 in human PCa cells, the study concludes that the heightened sensitivity to 8-FQ is likely associated with elevated levels of 15-LOX-1. In vivo experiments using immunosuppressed C57BL/6 mice bearing human PC-3 tumors revealed that 8-FQ, at a dosage of 10 mg/kg, exhibited strong antitumor effects with minimal side effects, indicating its potential as a promising therapeutic agent for PCa following further optimization.
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Affiliation(s)
- Mehrdad Aghasizadeh
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Tayebe Moghaddam
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Ahmad Reza Bahrami
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran; Industrial Biotechnology Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Hamid Sadeghian
- Department of Laboratory Sciences, School of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Jamal Alavi
- Department of Laboratory Sciences, School of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Tahmineh Kazemi
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Maryam M Matin
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran; Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran.
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Elgammal WE, Elkady H, Dahab MA, Mahdy HA, Hagras M, Nofal A, Alsfouk BA, Elkaeed EB, Eissa IH, Metwaly AM. Design and synthesis of thiadiazoles as anticancer, apoptotic, and VEGFR-2 inhibitors. Future Med Chem 2025; 17:915-927. [PMID: 40197130 DOI: 10.1080/17568919.2025.2485863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Accepted: 03/24/2025] [Indexed: 04/09/2025] Open
Abstract
BACKGROUND Vascular endothelial growth factor receptor (VEGFR-2) inhibitors are critical in cancer therapy due to their role in suppressing tumor angiogenesis. Herein, we report a new series of thiadiazole-based derivatives as potential VEGFR-2 inhibitors with promising anticancer activity. METHODS The synthesized compounds were evaluated for anti-proliferative activity against human cancer cell lines (HCT-116, MCF-7, and HepG-2), and WI-38 as normal cells. Sorafenib was used as a reference drug. VEGFR-2 inhibitory activity was determined, followed by cell cycle analysis, apoptosis assays, Q-RT-PCR analysis, and wound-healing assays. In silico molecular docking was conducted to explore binding interactions. RESULTS Among the tested compounds, 13b exhibited potent anti-proliferative activity (IC50: 3.98-11.81 µM) and strong VEGFR-2 inhibition (IC50: 41.51 nM), surpassing sorafenib (IC50: 53.32 nM). Cell cycle analysis revealed that 13b induced G2/M phase arrest in MCF-7 cells. Apoptosis levels increased from 2% to 52%, accompanied by a > 12-fold rise in the Bax/Bcl-2 ratio and activation of caspase-8/9. Additionally, 13b significantly suppressed MCF-7 cell migration, with only 5.28% wound closure. In silico studies confirmed its strong VEGFR-2 binding interactions. CONCLUSION Thiadiazole-based derivatives, particularly compound 13b, exhibit potent VEGFR-2 inhibition, anti-proliferative effects, apoptosis induction, and anti-migratory activity, supporting their potential as promising anticancer agents.
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Affiliation(s)
- Walid E Elgammal
- Department of Chemistry, Faculty of Science, Al-Azhar University, Nasr City, Cairo, Egypt
| | - Hazem Elkady
- Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
| | - Mohammed A Dahab
- Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
| | - Hazem A Mahdy
- Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
| | - Mohamed Hagras
- Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Ahmed Nofal
- Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Bshra A Alsfouk
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Eslam B Elkaeed
- Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh, Saudi Arabia
| | - Ibrahim H Eissa
- Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
| | - Ahmed M Metwaly
- Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
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6
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Grobbelaar C, Steenkamp V, Mabeta P. Vascular Endothelial Growth Factor Receptors in the Vascularization of Pancreatic Tumors: Implications for Prognosis and Therapy. Curr Issues Mol Biol 2025; 47:179. [PMID: 40136433 PMCID: PMC11941243 DOI: 10.3390/cimb47030179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 03/01/2025] [Accepted: 03/03/2025] [Indexed: 03/27/2025] Open
Abstract
In pancreatic cancer (PC), vascular endothelial growth factor (VEGF) and its primary receptor, vascular endothelial growth factor receptor (VEGFR)-2, are central drivers of angiogenesis and metastasis, with their overexpression strongly associated with poor prognosis. In some PC patients, VEGF levels correlate with disease stage, tumor burden, and survival outcomes. However, therapies targeting VEGF and VEGFR-2, including tyrosine kinase inhibitors (TKIs) and monoclonal antibodies, have demonstrated limited efficacy, partly due to the emergence of resistance mechanisms. Resistance appears to stem from the activation of alternative vascularization pathways. This review explores the multifaceted roles of VEGFRs in pancreatic cancer, including VEGFR-1 and VEGFR-3. Potential strategies to improve VEGFR-targeting therapies, such as combination treatments, the development of more selective inhibitors, and the use of biomarkers, are discussed as promising approaches to enhance treatment efficacy and outcomes.
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Affiliation(s)
- Craig Grobbelaar
- Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0002, South Africa;
| | - Vanessa Steenkamp
- Department of Pharmacology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0002, South Africa;
| | - Peace Mabeta
- Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0002, South Africa;
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7
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Samuel EMK, Sundaramurthi S, Hanumanthappa N, Nelamangalaramakrishnaiah VP. Diagnostic value of vascular endothelial growth factor (VEGF) levels in gastrointestinal cancers with ascites - A cross sectional study. Turk J Surg 2025; 41:78-84. [PMID: 40012327 DOI: 10.47717/turkjsurg.2025.6592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/28/2025]
Abstract
Objective Malignant ascites is suggestive of peritoneal carcinomatosis. The distinction between malignant and non-malignant ascites in a patient with malignancy is important, as it alters the management and prognosis. Current diagnostic methods are imaging, cytology, and diagnostic laparoscopy, all of which have low sensitivities. The vascular endothelial growth factor (VEGF) is essential for tumour growth and, hence, ascitic VEGF levels can be a diagnostic method for malignant ascites. Material and Methods This cross-sectional study was conducted in patients with gastrointestinal malignancies and ascites. The calculated sample size was 68 patients, who were divided into those who were truly positive or negative for malignant ascites based on a composite gold standard, comprising cytology, contrast enhanced computed tomography, and laparoscopy. The ascitic VEGF levels in these patients were compared. Results A total of 84 patients were enrolled, of whom 60.71% were found to have malignant ascites. It was found that the greater the volume of ascites, the greater the statistical likelihood of finding truly malignant ascites. The ascitic VEGF levels had a non-normal distribution, with median values of 783.64 and 41.12 pg/mL for malignant and non-malignant ascites (p<0.001). Using a receiver operating characteristics curve, a cut-off of 83.68 pg/mL was obtained, with a sensitivity of 100% and a specificity of 93.94%. Conclusion This study demonstrates that ascitic VEGF levels are significantly elevated in patients with gastrointestinal malignancies and malignant ascites and hence can reliably be used for diagnosing malignant ascites. This study also shows that massive ascites and well-differentiated tumours have a higher rate of peritoneal carcinomatosis.
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Affiliation(s)
| | - Sudharsanan Sundaramurthi
- Department of Surgery, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| | - Nandeesha Hanumanthappa
- Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
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Mansoori S, Hashemy SI, Eskandari M, Khorrami A, Homayouni M, Ghahremanloo A. Investigating the anticancer properties of urolithin B in triple negative breast cancer: In vivo and in vitro insights. Toxicol Appl Pharmacol 2025; 495:117224. [PMID: 39755131 DOI: 10.1016/j.taap.2024.117224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 12/27/2024] [Accepted: 12/30/2024] [Indexed: 01/06/2025]
Abstract
Breast cancer (BC) is a leading cause of cancer-related mortality among women worldwide, with incidence rates rising globally. Urolithin B (UB), a bioactive metabolite of ellagic acid, has demonstrated promising anticancer effects in various cancer models. This study aimed to evaluate the effects of UB on the growth, angiogenesis, and metastasis of BC cells using both in vivo and in vitro approaches. Cytotoxic effects of UB were assessed on MDA-MB-231 cells and normal HFF cells using the MTT assay. Scratch assays and gelatin zymography demonstrated UB's suppression of cell migration and reduced enzymatic activities of MMP-2 and MMP-9. In a xenograft mouse model, UB significantly reduced tumor growth, enhanced necrosis, and decreased vascularity in tumor tissues. It downregulated mRNA expression levels of VEGF, VEGFR, MMP-2, and MMP-9, indicating potent anti-angiogenic and anti-metastatic properties. Additionally, UB exhibited antioxidant effects by increasing total thiol content and the activities of superoxide dismutase (SOD) and catalase (CAT) while reducing malondialdehyde (MDA) levels in tumor tissues. In conclusion, our results highlight the anticancer potential of UB, through its ability to suppress the proliferation, angiogenesis, and metastatic properties of BC both in vitro and in vivo. Coupled with its antioxidant properties, UB emerges as a promising and safe candidate for further pre-clinical and clinical research and therapeutic applications in BC management.
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Affiliation(s)
- Saeide Mansoori
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Isaac Hashemy
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Moein Eskandari
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Azar Khorrami
- Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Masoud Homayouni
- Department of Biology, Mashhad Branch, Islamic Azad University, Mashhad, Iran.
| | - Atefeh Ghahremanloo
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Sharma P, Chida K, Wu R, Tung K, Hakamada K, Ishikawa T, Takabe K. VEGFA Gene Expression in Breast Cancer Is Associated With Worse Prognosis, but Better Response to Chemotherapy and Immunotherapy. World J Oncol 2025; 16:120-130. [PMID: 39850522 PMCID: PMC11750749 DOI: 10.14740/wjon1993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2025] [Accepted: 01/02/2025] [Indexed: 01/25/2025] Open
Abstract
Background Vascular endothelial growth factor-A (VEGFA) is a key inducer of angiogenesis, responsible for generating new blood vessels in the tumor microenvironment (TME) and facilitating metastasis. Notably, Avastin, which targets VEGFA, failed to demonstrate any significant benefit in clinical trials for breast cancer (BC). This study aimed to investigate the clinical relevance of VEGFA gene expression in BC. Methods A total of 7,336 BC patients across eight independent cohorts: ISPY2 (GSE173839), Sweden Cancerome Analysis Network-Breast (SCAN-B) (GSE96058), Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), GSE25066, GSE163882, GSE34138, GSE20194, and The Cancer Genome Atlas (TCGA), were analyzed. The calculated median VEGFA expression level was used to stratify these cohorts into high and low groups. Results High VEGFA was associated with worse disease-free, disease-specific, and overall survival in the METABRIC cohort, with findings supported by the SCAN-B cohort, which also showed worse overall survival (all P < 0.02). High VEGFA expression was seen in triple-negative breast cancer (TNBC) but not in BC with lymph node metastasis. Additionally, there was a significant correlation between high VEGFA expression and higher silent and non-silent mutations, single-nucleotide variant (SNV) neoantigens, homologous recombination defect, intratumoral heterogeneity, in the TCGA cohort. In the TCGA, METABRIC, and SCAN-B cohorts, high VEGFA BC was also associated with higher cell proliferation: higher Ki67 gene expression, higher Nottingham histological grade, and consistent enrichment of all the Hallmark cell proliferation-related gene sets. Unexpectedly, the angiogenesis gene set was not enriched in any of the cohorts and showed no association with infiltrations of lymphatic or blood vascular endothelial cells besides pericytes. High VEGFA BC had significantly less infiltration of anti-cancer immune cells but higher infiltration of pro-cancer immune cells in TCGA, METABRIC, and SCAN-B cohorts. Interestingly, BC, which had a pathological complete response (pCR) after anthracycline- and taxane-based neoadjuvant therapy, was associated with significantly heightened VEGFA expression in both estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)- and TNBC subtypes in the GSE25066 cohort and after immunotherapy in ER+/ HER2- subtype, but not TNBC in the ISPY2 cohort. Conclusions Our research indicates that high VEGFA BC confers high cell proliferation, reduced immune cell infiltration, and poorer survival, but allows better response to anthracycline- and taxane-based chemotherapy, and immunotherapy.
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Affiliation(s)
- Pia Sharma
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA
| | - Kohei Chida
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Rongrong Wu
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan
| | - Kaity Tung
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14203, USA
| | - Kenichi Hakamada
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Takashi Ishikawa
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14203, USA
- Department of Breast and Thyroid Surgery, Yokohama City University Medical Center, Yokohama, Kanagawa, Japan
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8520, Japan
- Department of Breast Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA
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Kim K, Lim C, Kim S, Lim H, Hyun SH, Kang BT, Chang D, Lee N. Case report: Transarterial chemoembolization for nasal hemangiosarcoma in a dog. Front Vet Sci 2025; 11:1505671. [PMID: 39906045 PMCID: PMC11792167 DOI: 10.3389/fvets.2024.1505671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 12/24/2024] [Indexed: 02/06/2025] Open
Abstract
This report outlines the use of transarterial chemoembolization (TACE) to treat a nasal tumor in a 10-year-old Welsh Corgi. The dog initially presented with persistent nasal discharge and facial deformity, which led to a diagnosis of nasal hemangiosarcoma. Although initial treatments with radiotherapy and chemotherapy provided temporary relief, the symptoms reappeared 11 months later. As a palliative measure, TACE was administered, utilizing carboplatin as the chemotherapeutic agent and gel foam as the embolic material. The procedure successfully reduced the tumor size and alleviated the dog's symptoms. Follow-up CT scans at 1, 3, 7, and 10 months, demonstrated sustained tumor shrinkage. Interestingly, there was no reperfusion of the embolized vessels, indicating a prolonged therapeutic effect. No significant complications were observed during follow-up. This case highlights the potential of TACE as a palliative option for managing recurrent nasal tumors in dogs, especially when other treatments have limited efficacy. Further research is needed to establish TACE guidelines for treating nasal tumors in veterinary medicine.
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Affiliation(s)
- Keunho Kim
- Section of Veterinary Medical Imaging, College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea
| | - Changgyu Lim
- Section of Veterinary Medical Imaging, College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea
| | - Songyi Kim
- Section of Veterinary Medical Imaging, College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea
| | - Hearang Lim
- Section of Veterinary Medical Imaging, College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea
| | - Sang-Hwan Hyun
- Vet-ICT Convergence Education and Research Center (VICERC), Chungbuk National University, Cheongju, Republic of Korea
| | - Byeong-Teck Kang
- Laboratory of Veterinary Internal Medicine, College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea
| | - Dongwoo Chang
- Section of Veterinary Medical Imaging, College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea
| | - Namsoon Lee
- Section of Veterinary Medical Imaging, College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea
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Wang R, Liu G, Wang K, Pan Z, Pei Z, Hu X. Hypoxia signature derived from tumor-associated endothelial cells predict prognosis in gastric cancer. Front Cell Dev Biol 2025; 13:1515681. [PMID: 39901877 PMCID: PMC11788339 DOI: 10.3389/fcell.2025.1515681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 01/03/2025] [Indexed: 02/05/2025] Open
Abstract
Background A hypoxic metabolism environment in the tumors is often associated with poor prognostic events such as tumor progression and treatment resistance. In gastric cancer, the mechanism of how hypoxia metabolism affects the tumor microenvironment and immunotherapy efficacy remains to be elucidated. Methods We used the bulk-mapping method to analyze the signatures correlated with the response of immunotherapy in the single-cell dataset. Cellular, pathway, and gene were systematically analyzed in both single-cell and bulk validation datasets. Results The most significant cell proportion difference between the response and non-response groups was in endothelial cells, which represent the malignant cells. VWF was specifically overexpressed in endothelial cells and was the hub gene of differential genes. EPAS1 was a VWF trans-regulated gene and highly positively correlated with VWF in expression. Knockdown experiments demonstrated that siVWF reduced the expression of VWF, EPAS1, and HIF1A, as well as the synthesis of lactate and adenosine which are indicators of hypoxic metabolism. These results suggest that the overexpression of core malign endothelial genes such as VWF drives hypoxic metabolism in tumors and creates an immunosuppressive environment that reduces the efficacy of immunotherapy. The adverse prognosis of the hypoxia signature was validated in the bulk cohort and significance was further enhanced after selecting core genes and combined survival weight scoring. Conclusion In summary, high expression of the malignant endothelial cell driver genes VWF and EPAS1 enhances hypoxic metabolism, and malignant cell-immune cell interactions suppress the immune response. Therefore, the two core genes of hypoxic metabolism might represent potential therapeutic and predicting biomarkers for immunotherapy of gastric cancer in the future.
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Affiliation(s)
- Ruiheng Wang
- Surgical Ward, The Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Guijun Liu
- Heilongjiang University of Chinese Medicine, Harbin, China
- Department of administrative, The Fourth Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Ke Wang
- Endoscopy Room, First Affiliated Hospital of Jiamusi University, Jiamusi, China
| | - Zhanglei Pan
- Surgical Ward, The Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Zhihua Pei
- Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan, China
| | - Xijiao Hu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
- Postdoctoral Research Station of Heilongjiang Academy of Traditional Chinese Medicine, Harbin, China
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12
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Ibrahem E, Osman A, Taha H, Abo El-Maati MF, Sitohy B, Sitohy M. Anticarcinogenic cationic peptides derived from tryptic hydrolysis of β-lactoglobulin. Front Mol Biosci 2025; 11:1444457. [PMID: 39866644 PMCID: PMC11757936 DOI: 10.3389/fmolb.2024.1444457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 12/09/2024] [Indexed: 01/28/2025] Open
Abstract
Introduction This study investigated the tryptic hydrolysis of β-lactoglobulin (BLG) for 30, 60, 90, and 120 min at 1/200 E/S (enzyme/substrate ratio, w/w) to prepare potentially anticarcinogenic peptides. Methods The properties of hydrolysates were characterized, including degree of hydrolysis, free amino acids, SDS-PAGE, FTIR, and antioxidant activity employing DPPH-assay, β-carotene/linoleic acid, and FRAP assay. Results BLG tryptic hydrolysate produced after 60 min hydrolysis recorded the highest antioxidant activity, and LCMS analysis revealed 162 peptides of molecular masses ranging from 800 to 5671Da, most of them are of hydrophobic nature. Within the low-MW peptide group (24 peptides), there were nine hydrophobic basic (HB) and seven hydrophobic acidic (HA), representing 38% and 29%, respectively. The HB peptides may be responsible for the considerable biological activity of the hydrolysate. With dominant basic character supporting the carcinogenic activity of this hydrolysate. The in vitro anticancer activity against Mcf-7, Caco-2, and A-549 human cancer cell lines proliferation by MTT assay recorded IC50% at 42.8, 76.92, and 45.93 μg/mL, respectively. Treating each cell line with IC50% of the hydrolysate for 24 h increased the apoptosis by enhancing the expression of caspase-9 by 5.66, 7.97, and 3.28 folds over the untreated control and inhibited angiogenesis by reducing VEGFR-2 expression by about 56, 76, and 70%, respectively, indicating strong anticancer and antiangiogenic actions on human cancer cells. BLG tryptic hydrolysate may serve as a natural anticarcinogenic agent. The results of this study demonstrated that BLG hydrolysates have direct anticancer and antiangiogenic effects on human cancer cells. The chemical composition and characteristics of the BLG tryptic hydrolysate influence these biological and anticancer activities. The tryptic hydrolysates were generally effective against the three cancer cell lines studied (Mcf-7, Caco-2, and A-549). This effectiveness was assessed by measuring cell proliferation using the MTT assay and by evaluating their impact on angiogenesis through inhibition of VEGFR-2 activity. Discussion Future studies may focus on enhancing the anticarcinogenic effectiveness of the peptides by isolating and evaluating the most prominent individual peptide and varying the treatment conditions.
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Affiliation(s)
- Eman Ibrahem
- Department of Biochemistry, Faculty of Agriculture, Zagazig University, Zagazig, Egypt
| | - Ali Osman
- Department of Biochemistry, Faculty of Agriculture, Zagazig University, Zagazig, Egypt
| | - Hefnawy Taha
- Department of Biochemistry, Faculty of Agriculture, Zagazig University, Zagazig, Egypt
| | | | - Basel Sitohy
- Department of Clinical Microbiology, Infection and Immunology, Umeå University, Umeå, Sweden
- Department of Diagnostics and Intervention, Oncology, Umeå University, Umeå, Sweden
| | - Mahmoud Sitohy
- Department of Biochemistry, Faculty of Agriculture, Zagazig University, Zagazig, Egypt
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Song M, Elkamhawy A, Noh W, Abdelazem AZ, Park Y, Sivaraman A, Bertleuova A, Atef D, Lee K. Pyrimidine scaffold dual-target kinase inhibitors for cancer diseases: A review on design strategies, synthetic approaches, and structure-activity relationship (2018‒2023). Arch Pharm (Weinheim) 2025; 358:e2400163. [PMID: 39828961 DOI: 10.1002/ardp.202400163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 12/11/2024] [Accepted: 12/18/2024] [Indexed: 01/22/2025]
Abstract
Cancer, the second leading cause of death globally, causes a significant threat to life. Despite advancements in the treatment of cancer, persistent challenges include severe side effects and the emergence of acquired drug resistance. Additionally, many traditional chemotherapy drugs show restricted efficacy and high toxicity, primarily attributed to their lack of selectivity. Thus, the development of drugs targeting protein kinases has emerged as a noteworthy priority for addressing human cancers. Medicinal chemists have shown considerable interest in the development of dual drug candidates as a strategy to create medicines that are safer, more efficient, and cost-effective. Furthermore, the Food and Drug Administration (FDA) has approved several dual-target drugs for anticancer treatment, emphasizing their lower risks of drug interactions and improved pharmacokinetics and safety profiles. This review focuses on the synthetic efforts, design strategies, and structure-activity relationship of the pyrimidine scaffold-based dual kinase inhibitors developed with anticancer potential within the recent 6 years (2018‒2023). Collectively, these strategies are expected to offer fresh perspectives on the future directions of pyrimidine-based dual-target kinase drug design, potentially advancing cancer therapeutics.
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Affiliation(s)
- Moeun Song
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Seoul, Republic of Korea
| | - Ahmed Elkamhawy
- Department of Chemistry, School of Sciences and Humanities, Nazarbayev University, Astana, Kazakhstan
| | - Woojeong Noh
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Seoul, Republic of Korea
| | - Ahmed Z Abdelazem
- Biotechnology & Life Sciences Department, Faculty of Postgraduate Studies for Advanced Sciences, Beni-Suef University, Beni, suef, Egypt
| | - Younggeun Park
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Seoul, Republic of Korea
| | - Aneesh Sivaraman
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Seoul, Republic of Korea
| | - Arailym Bertleuova
- Department of Chemistry, School of Sciences and Humanities, Nazarbayev University, Astana, Kazakhstan
| | - Dalia Atef
- Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Kyeong Lee
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Seoul, Republic of Korea
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Kaviyaprabha R, Miji TV, Suseela R, Muthusami S, Thangaleela S, Almoallim HS, Sivakumar P, Bharathi M. Screening miRNAs to Hinder the Tumorigenesis of Renal Clear Cell Carcinoma Associated with KDR Expression. Curr Cancer Drug Targets 2025; 25:183-203. [PMID: 39289946 DOI: 10.2174/0115680096321287240826065718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 08/12/2024] [Accepted: 08/16/2024] [Indexed: 09/19/2024]
Abstract
INTRODUCTION This study delved to understand the role of Kinase Insert Domain Receptor (KDR) and its associated miRNAs in renal cell carcinoma through an extensive computational analysis. The potential of our findings to guide future research in this area is significant. METHODS Our methods, which included the use of UALCAN and GEPIA2 databases, as well as miRDB, MirDIP, miRNet v2.0, miRTargetLink, MiEAA v2.1, TarBase v8.0, INTERNET, and miRTarBase, were instrumental in identifying the regulation of miRNA associated with KDR expression. The predicted miRNA was validated with the TCGA-KIRC patients' samples by implementing CancerMIRNome. The TargetScanHuman v8.0 was implemented to identify the associations between human miRNAs and KDR. A Patch Dock server analyzed the interactions between hsa-miR-200c-3p and KDR. RESULTS The KDR expression rate was investigated in the Kidney Renal Cell Carcinoma (KIRC) samples, and adjacent normal tissues revealed that the expression rate was significantly higher than the normal samples, which was evident from the strong statistical significance (P = 1.63e-12). Likely, the KDR expression rate was estimated as high at tumor grade 1 and gradually decreased till the metastasis grade, reducing the survival rate of the KIRC patients. To identify these signals early, we predicted a miRNA that could alter the expression of KDR. Furthermore, we uncovered the potential associations between miR-200c-3p expressions by regulating KDR towards the progression of KIRC. DISCUSSION Upon examining the outcome, it became evident that miR-200c-3p was significantly downregulated in KIRC compared to the normal samples. Moreover, the negative correlation was obtained for hsa-miR-200c-3p (R = - 0.276) along with the KDR expression describing that the increased rate of hsamiR- 200c-3p might reduce the KDR expression rate, which may suppress the KIRC initiation or progression. CONCLUSION The in-silico analysis indicated that the significant increase in KDR expression during the initiation of KIRC could serve as an early diagnostic marker. Moreover, KDR could be utilized to identify advancements in KIRC stages. Additionally, hsa-miR-200c-3p was identified as a potential regulator capable of downregulating and upregulating KDR expression among the 24 miRNAs screened. This finding holds promise for future research endeavors. Concurrent administration of the FDA-approved 5- fluorouracil with KIRC drugs, such as sorafenib, zidovudine, and everolimus, may have the potential to enhance the therapeutic efficacy in downregulating hsa-miR-200c-3p. However, further in vitro studies are imperative to validate these findings and gain a comprehensive understanding of the intricate regulatory interplay involving hsa-miR-200c-3p, KDR, 5-fluorouracil, and other FDA-approved drugs for the treatment of KIRC. This will facilitate the identification of KIRC stage progression and its underlying preventative mechanisms.
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Affiliation(s)
- Rangaraj Kaviyaprabha
- Centre for Bioinformatics, Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, 641021, India
| | - Thandaserry Vasudevan Miji
- Centre for Bioinformatics, Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, 641021, India
| | - Rangaraj Suseela
- Centre for Cancer Research, Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, 641021, India
| | - Sridhar Muthusami
- Centre for Cancer Research, Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, 641021, India
| | - Subramanian Thangaleela
- Institute of Biotechnology, Department of Medical Biotechnology and Integrative Physiology, Saveetha School of Engineering, Saveetha Institute of Medical and Technical Sciences, Thandalam, Chennai, 602 105, Tamil Nadu, India
| | - Hesham S Almoallim
- Department of Oral and Maxillofacial Surgery, College of Dentistry, King Saud University, PO Box-60169, Riyadh -11545, Saudi Arabia
| | - Priyadarshini Sivakumar
- Department of Microbiology, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, 641021, India
| | - Muruganantham Bharathi
- Centre for Bioinformatics, Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, 641021, India
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Evans ST, Jani Y, Jansen CS, Yildirim A, Kalemoglu E, Bilen MA. Understanding and overcoming resistance to immunotherapy in genitourinary cancers. Cancer Biol Ther 2024; 25:2342599. [PMID: 38629578 PMCID: PMC11028033 DOI: 10.1080/15384047.2024.2342599] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/19/2024] Open
Abstract
The introduction of novel immunotherapies has significantly transformed the treatment landscape of genitourinary (GU) cancers, even becoming the standard of care in some settings. One such type of immunotherapy, immune checkpoint inhibitors (ICIs) like nivolumab, ipilimumab, pembrolizumab, and atezolizumab play a pivotal role by disturbing signaling pathways that limit the immune system's ability to fight tumor cells. Despite the profound impact of these treatments, not all tumors are responsive. Recent research efforts have been focused on understanding how cancer cells manage to evade the immune response and identifying the possible mechanisms behind resistance to immunotherapy. In response, ICIs are being combined with other treatments to reduce resistance and attack cancer cells through multiple cellular pathways. Additionally, novel, targeted strategies are currently being investigated to develop innovative methods of overcoming resistance and treatment failure. This article presents a comprehensive overview of the mechanisms of immunotherapy resistance in GU cancers as currently described in the literature. It explores studies that have identified genetic markers, cytokines, and proteins that may predict resistance or response to immunotherapy. Additionally, we review current efforts to overcome this resistance, which include combination ICIs and sequential therapies, novel insights into the host immune profile, and new targeted therapies. Various approaches that combine immunotherapy with chemotherapy, targeted therapy, vaccines, and radiation have been studied in an effort to more effectively overcome resistance to immunotherapy. While each of these combination therapies has shown some efficacy in clinical trials, a deeper understanding of the immune system's role underscores the potential of novel targeted therapies as a particularly promising area of current research. Currently, several targeted agents are in development, along with the identification of key immune mediators involved in immunotherapy resistance. Further research is necessary to identify predictors of response.
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Affiliation(s)
- Sean T Evans
- Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Yash Jani
- Undergraduate studies, Mercer University, Macon, GA, USA
| | - Caroline S Jansen
- Medical Scientist Training Program, Emory University School of Medicine, Atlanta, GA, USA
- Genitourinary Medical Oncology Program, Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA
| | - Ahmet Yildirim
- Genitourinary Medical Oncology Program, Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA
| | - Ecem Kalemoglu
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA
- Department of Basic Oncology, Health Institute of Ege University, Izmir, Turkey
| | - Mehmet Asim Bilen
- Genitourinary Medical Oncology Program, Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA
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Lekpor CE, Botchway FA, Driss A, Bashi A, Abrahams AD, Kusi KA, Futagbi G, Alema-Mensah E, Agbozo W, Solomon W, Harbuzariu A, Adjei AA, Stiles JK. Circulating biomarkers associated with pediatric sickle cell disease. Front Mol Biosci 2024; 11:1481441. [PMID: 39749215 PMCID: PMC11694143 DOI: 10.3389/fmolb.2024.1481441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 10/30/2024] [Indexed: 01/04/2025] Open
Abstract
Introduction Sickle cell disease (SCD) is a genetic blood disorder caused by a mutation in the HBB gene, which encodes the beta-globin subunit of hemoglobin. This mutation leads to the production of abnormal hemoglobin S (HbS), causing red blood cells to deform into a sickle shape. These deformed cells can block blood flow, leading to complications like chronic hemolysis, anemia, severe pain episodes, and organ damage. SCD genotypes include HbSS, HbSC (HbC is an abnormal variant of hemoglobin), and HbS/β-thalassemia. Sickle cell trait (SCT), HbAS, represents the carrier state, while other hemoglobin variants include HbCC, HbAC, and the normal HbAA. Over 7.5 million people worldwide live with SCD, with a high mortality rate in sub-Saharan Africa, including Ghana. Despite its prevalence, SCD is underdiagnosed and poorly managed, especially in children. Characterized by intravascular hemolysis, SCD leads to oxidative stress, endothelial activation, and systemic inflammation. Identifying circulating blood biomarkers indicative of organ damage and systemic processes is vital for understanding SCD and improving patient management. However, research on biomarkers in pediatric SCD is limited and few have been identified and validated. This study explores specific circulating biomarkers in pediatric SCD in Ghana (West Africa), hypothesizing that inflammatory and neuronal injury markers in children with SCD could predict disease outcomes. Methods Clinical data were collected from 377 children aged 3-8 years with various Hb genotypes, including SCD and SCT, at Korle-Bu Teaching Hospital in Accra, Ghana (2021-2022). A total of 80 age- and sex-matched subjects were identified. A cross-sectional study utilized a multiplexed immunoassay procedure to evaluate serum biomarkers, including cytokines, chemokines, vascular injury markers, systemic inflammation markers, cell-free heme scavengers, brain-derived neurotrophic factor (BDNF), and angiogenic factors. Results Elevated levels of BDNF, Ang-2, CXCL10, CCL11, TNF-α, IL-6, IL-10, IL12p40, ICAM-1, VCAM-1, Tie-2, and VEGFA were observed in HbSS subjects, correlating with hemoglobin level, leukocyte, and erythrocyte counts. Heme scavengers like HO-1, hemopexin, and haptoglobin also correlated with these parameters. ROC and AUC analyses demonstrated the potential of these biomarkers in predicting SCD outcomes. Conclusion These findings suggest that there are significant differences between biomarker expression among the different genotypes examined. We conclude that a predictive algorithm based on these biomarkers could be developed and validated through longitudinal assessment of within-genotype differences and correlation of the data with disease severity or outcomes. With such a tool one can enhance SCD management and improve patient outcomes. This approach may pave the way for personalized interventions and better clinical care for pediatric SCD patients.
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Affiliation(s)
- Cecilia Elorm Lekpor
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, United States
- Department of Pathology, Korle-Bu Teaching Hospital, University of Ghana Medical School, Accra, Ghana
- Department of Animal Biology and Conservation Sciences, University of Ghana, Accra, Ghana
| | | | - Adel Driss
- Department of Physiology, Morehouse School of Medicine, Atlanta, GA, United States
| | - Alaijah Bashi
- Department of Physiology, Morehouse School of Medicine, Atlanta, GA, United States
| | - Afua D. Abrahams
- Department of Pathology, Korle-Bu Teaching Hospital, University of Ghana Medical School, Accra, Ghana
| | - Kwadwo Asamoah Kusi
- Department of Immunology, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana
| | - Godfred Futagbi
- Department of Animal Biology and Conservation Sciences, University of Ghana, Accra, Ghana
| | - Ernest Alema-Mensah
- Community Health and Preventive Medicine, Morehouse School of Medicine, Atlanta, GA, United States
| | - William Agbozo
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, United States
| | - Wesley Solomon
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, United States
| | | | - Andrew A. Adjei
- Department of Pathology, Korle-Bu Teaching Hospital, University of Ghana Medical School, Accra, Ghana
| | - Jonathan K. Stiles
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, United States
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Mederle AL, Stana LG, Ilie AC, Borza C, Streian CG, Nistor D, Cerbulescu T, Belovan B, Lascu A. Efficacy and Safety of Pazopanib in the Treatment of Thyroid Cancer: A Systematic Review. Biomedicines 2024; 12:2820. [PMID: 39767725 PMCID: PMC11673424 DOI: 10.3390/biomedicines12122820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 12/07/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
Pazopanib, a multi-targeted tyrosine kinase inhibitor, has been explored for its efficacy in treating various subtypes of thyroid cancer, including differentiated thyroid carcinoma (DTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC). This systematic review assesses the efficacy and safety of pazopanib, focusing on the progression-free survival (PFS), overall survival (OS), and response rates and adverse events. A comprehensive search was conducted in databases including PubMed, Scopus, and Web of Science up to October 2024 to identify randomized controlled trials and phase II clinical trials that investigated the use of pazopanib in thyroid cancer. The PRISMA guidelines were followed for data extraction and quality assessment. The review included six studies encompassing 289 patients, presenting a comprehensive overview of pazopanib's application across different thyroid cancer subtypes. The studies reported median PFS rates ranging from 2.1 to 11.7 months and median OS rates ranging from 5.7 months to not reached. The partial response rates varied from 5% to 49%. Adverse events were common, with hypertension occurring in up to 71.7% of patients, and fatigue and diarrhea were also frequently reported. Grade 3-5 adverse events led to treatment discontinuations in up to 14% of patients. Pazopanib shows variable efficacy across thyroid cancer types, offering significant benefits in MTC and refractory DTC in terms of PFS and OS but limited impact in ATC. The adverse event profile necessitates careful management, particularly regarding hypertension and other treatment-related toxicities. Further studies are required to refine the therapeutic protocols for pazopanib, exploring combination therapies that may enhance its efficacy and reduce the adverse outcomes.
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Affiliation(s)
- Alexandra Laura Mederle
- Surgery Clinic, County Emergency Hospital “Pius Brinzeu”, 300723 Timisoara, Romania;
- Faculty of Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Loredana Gabriela Stana
- Department I, Discipline of Anatomy and Embriology, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania;
| | - Adrian Cosmin Ilie
- Department III Functional Sciences, Division of Public Health and Management, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania;
| | - Claudia Borza
- Department of Functional Sciences, Discipline of Physiopathology, Faculty of Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (C.B.); (A.L.)
- Centre for Translational Research and Systems Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Centre of Cognitive Research in Pathological Neuro-Psychiatry (NEUROPSY-COG), “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Caius Glad Streian
- Department VI Cardiology-Cardiovascular Surgery, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania;
- Advanced Research Center of the Institute for Cardiovascular Diseases, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Institute for Cardiovascular Diseases of Timisoara, Clinic for Cardiovascular Surgery, 300310 Timisoara, Romania
| | - Daciana Nistor
- Department of Functional Sciences, Physiology and Biotechnologies (CIFBIOTEH), “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Centre for Gene and Cellular Therapies in Cancer, 3000723 Timisoara, Romania
| | - Teodor Cerbulescu
- Department III—Microscopic Morphology, Discipline of Cellular and Molecular Biology, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Square 2, 300041 Timisoara, Romania;
| | - Biliana Belovan
- Doctoral School, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Square 2, 300041 Timisoara, Romania;
| | - Ana Lascu
- Department of Functional Sciences, Discipline of Physiopathology, Faculty of Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (C.B.); (A.L.)
- Centre for Translational Research and Systems Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Institute for Cardiovascular Diseases of Timisoara, Clinic for Cardiovascular Surgery, 300310 Timisoara, Romania
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Cannavo A, Gelzo M, Vinciguerra C, Corbi G, Maglione M, Tipo V, Giannattasio A, Castaldo G. Serum endocan (ESM-1) as diagnostic and prognostic biomarker in Multisystem inflammatory syndrome in children (MIS-C). Cytokine 2024; 184:156797. [PMID: 39488191 DOI: 10.1016/j.cyto.2024.156797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 10/08/2024] [Accepted: 10/27/2024] [Indexed: 11/04/2024]
Abstract
Endothelial-cell-specific molecule-1 (ESM-1) also called endocan is a well-known biomarker for detecting inflammation, endothelial dysfunction (ED), and cardiovascular (CV) risk in COVID-19 patients. Upon SARS-CoV-2 infection, a small percentage of children develop Multisystem Inflammatory Syndrome in children (MIS-C). Whether endocan can be used as a biomarker of MIS-C is unknown. In this study, we assessed ESM-1 levels in MIS-C (n = 19) and healthy controls (HC; n = 17). We observed a significant increase in serum ESM-1 levels in MIS-C vs HC (p = 0.0074). In addition, ROC curve analysis demonstrated that this factor has a reasonable discriminatory power between MIS-C patients and HC (AUC of 0.7585). Notably, after one week of hospitalization and care, ESM-1 levels decreased, and this reduction was observed also for other inflammatory and pro-thrombotic markers like C-reactive protein, procalcitonin, fibrinogen, D-dimer, and ferritin, suggesting a general recovery trend in MIS-C patients. In fact, we observed that serum ESM-1 levels positively correlated with procalcitonin (PCT) (r = 0.468; p = 0.043). Finally, logistic regression analysis demonstrated an association between endocan levels and cardiac complications like myocarditis. Therefore, this study suggests that ESM-1 is a valuable diagnostic and prognostic biomarker in patients with MIS-C that may help identify those MIS-C patients at higher risk for cardiovascular complications and guide treatment strategies.
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Affiliation(s)
- Alessandro Cannavo
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy.
| | - Monica Gelzo
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy; CEINGE-Biotecnologie Avanzate S.c.a.r.l., Naples, Italy.
| | - Caterina Vinciguerra
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Graziamaria Corbi
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Marco Maglione
- Pediatric Emergency and Short Stay Unit, Santobono-Pausilipon Children's Hospital, Naples, Italy
| | - Vincenzo Tipo
- Pediatric Emergency and Short Stay Unit, Santobono-Pausilipon Children's Hospital, Naples, Italy
| | - Antonietta Giannattasio
- Pediatric Emergency and Short Stay Unit, Santobono-Pausilipon Children's Hospital, Naples, Italy
| | - Giuseppe Castaldo
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy; CEINGE-Biotecnologie Avanzate S.c.a.r.l., Naples, Italy
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Banerjee N, Roy L, Panda S, Roychowdhury T, Chatterjee S. In Silico-Designed G-Quadruplex Targeting Peptide Attenuates VEGF-A Expression, Preventing Angiogenesis in Cancer Cells. Chem Biol Drug Des 2024; 104:e70018. [PMID: 39704035 DOI: 10.1111/cbdd.70018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 10/28/2024] [Accepted: 10/31/2024] [Indexed: 12/21/2024]
Abstract
Vascular endothelial growth factor-A (VEGF-A) is a growth factor and pluripotent cytokine that promotes angiogenesis in cancer cells, transitioning to an angiogenic phenotype. The binding of VEGF-A protein to VEGF receptors (VEGFR-1 and VEGFR-2) initiates a cascade of events that stimulates angiogenesis by facilitating the migration and enhancing the permeability of endothelial cells. The proximal promoter of the VEGF gene encompasses a 36-base pair region (from -85 to -50) that can form a stable G-quadruplex (G4) structure in specific conditions. The activity of the VEGF promoter is reliant on this structure. During cancer progression, the VEGF-A G4 succumbs to cellular pressure and fails to maintain a stable structure. This shifts the balance to form a duplex structure, increasing the transcription rate. Earlier research has tried to develop small-molecule ligands to target and stabilise G4, demonstrating the possibility of suppressing VEGF expression. However, they either lack specificity or toxic. Peptides, on the other hand, are significantly less studied as G4 binders. Here, we designed a peptide that successfully binds and stabilises the VEGF-A G4 while reducing its gene expression. This further alters the expression fate of the VEGF-A signalling cascade and blocks angiogenesis in cancer cells. We employed high-resolution nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics simulation to elucidate the chemical details of G4-peptide interaction. In addition, we used qPCR and western blot techniques to investigate the expression pattern of the molecules implicated in the VEGF-A signalling cascade. The study explores the intricate relationship between peptides and quadruplex structures, revealing valuable insights that can improve the design of pharmacophores targeting the dynamic quadruplex structure. The results of our study are encouraging, opening possibilities for advancements in, the characterisation and optimisation of peptides as G-quadruplex ligands in view of their potential therapeutic uses.
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Affiliation(s)
- Nilanjan Banerjee
- Non-Coding Genome Group, Department of Structural Biology, CEITEC-Central European Institute of Technology, Brno, Czech Republic
| | - Laboni Roy
- Department of Biological Science, Bose Institute, Unified Academic Campus, Kolkata, India
| | - Suman Panda
- Department of Biological Science, Bose Institute, Unified Academic Campus, Kolkata, India
| | - Tanaya Roychowdhury
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Subhrangsu Chatterjee
- Department of Biological Science, Bose Institute, Unified Academic Campus, Kolkata, India
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20
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Sankarapandian V, Rajendran RL, Miruka CO, Sivamani P, Maran BAV, Krishnamoorthy R, Gangadaran P, Ahn BC. A review on tyrosine kinase inhibitors for targeted breast cancer therapy. Pathol Res Pract 2024; 263:155607. [PMID: 39326367 DOI: 10.1016/j.prp.2024.155607] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 09/09/2024] [Accepted: 09/24/2024] [Indexed: 09/28/2024]
Abstract
Breast cancer is a heterogeneous disease with complex molecular pathogenesis. Overexpression of several tyrosine kinase receptors is associated with poor prognosis, therefore, they can be key targets in breast cancer therapy. Tyrosine kinase inhibitors (TKIs) have emerged as leading agents in targeted cancer therapy due to their effectiveness in disrupting key molecular pathways involved in tumor growth. TKIs target various tyrosine kinases, including the human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), Vascular endothelial growth factor receptor (VEGFR), anaplastic lymphoma kinase (ALK), vascular endothelial growth factor receptor (VEGFR)-associated multi-targets, rearranged during transfection (RET), fibroblast growth factor receptor (FGFR), receptor tyrosine kinase-like orphan signal 1 (ROS1), Mitogen-activated protein kinase (MAPK), and tropomyosin receptor kinase (TRK). These drugs target the tyrosine kinase domain of receptor tyrosine kinases and play a vital role in proliferation and migration of breast cancer cells. Several TKIs, including lapatinib, neratinib, and tucatinib, have been developed and are currently used in clinical settings, often in combination with chemotherapy, endocrine therapy, or other targeted agents. TKIs have demonstrated remarkable benefits in enhancing progression-free and overall survival in patients with breast cancer and have become a standard of care for this population. This review provides an overview of TKIs currently being examined in preclinical studies and clinical trials, especially in combination with drugs approved for breast cancer treatment. TKIs have emerged as a promising therapeutic option for patients with breast cancer and hold potential for treating other breast cancer subtypes. The development of new TKIs and their integration into personalized treatment strategies will continue to shape the future of breast cancer therapy.
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Affiliation(s)
- Vidya Sankarapandian
- Department of Microbiology and Immunology, Kampala International University, Western Campus, Box 20000, Uganda
| | - Ramya Lakshmi Rajendran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea; Cardiovascular Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Conrad Ondieki Miruka
- Department of Biochemistry, Kampala International University, Western Campus, Box 20000, Uganda
| | - Poornima Sivamani
- Department of Pharmacology and Clinical pharmacology, Christian Medical College, Vellore 632004, India
| | - Balu Alagar Venmathi Maran
- Graduate School of Integrated Science and Technology, Nagasaki University, 1-14 Bunkyomachi, Nagasaki 852-8521, Japan
| | - Rajapandiyan Krishnamoorthy
- Department of Food Science and Nutrition, College of Food and Agriculture Sciences, King Saud University, Riyadh 11451, Kingdom of Saudi Arabia
| | - Prakash Gangadaran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea; BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Sciences, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea; Cardiovascular Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea..
| | - Byeong-Cheol Ahn
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea; BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Sciences, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea; Department of Nuclear Medicine, Kyungpook National University Hospital, Daegu 41944, Republic of Korea; Cardiovascular Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea..
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21
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Zhou Y, Li C, Chen X, Zhao Y, Liao Y, Huang P, Wu W, Nieto NS, Li L, Tang W. Development of folate receptor targeting chimeras for cancer selective degradation of extracellular proteins. Nat Commun 2024; 15:8695. [PMID: 39379374 PMCID: PMC11461649 DOI: 10.1038/s41467-024-52685-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 09/19/2024] [Indexed: 10/10/2024] Open
Abstract
Targeted protein degradation has emerged as a novel therapeutic modality to treat human diseases by utilizing the cell's own disposal systems to remove protein target. Significant clinical benefits have been observed for degrading many intracellular proteins. Recently, the degradation of extracellular proteins in the lysosome has been developed. However, there have been limited successes in selectively degrading protein targets in disease-relevant cells or tissues, which would greatly enhance the development of precision medicine. Additionally, most degraders are not readily available due to their complexity. We report a class of easily accessible Folate Receptor TArgeting Chimeras (FRTACs) to recruit the folate receptor, primarily expressed on malignant cells, to degrade extracellular soluble and membrane cancer-related proteins in vitro and in vivo. Our results indicate that FRTAC is a general platform for developing more precise and effective chemical probes and therapeutics for the study and treatment of cancers.
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Affiliation(s)
- Yaxian Zhou
- Lachman Institute of Pharmaceutical Development, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Chunrong Li
- Lachman Institute of Pharmaceutical Development, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Xuankun Chen
- Lachman Institute of Pharmaceutical Development, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Yuan Zhao
- Lachman Institute of Pharmaceutical Development, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Yaxian Liao
- Department of Chemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Penghsuan Huang
- Department of Chemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Wenxin Wu
- Department of Chemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Nicholas S Nieto
- Lachman Institute of Pharmaceutical Development, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Lingjun Li
- Lachman Institute of Pharmaceutical Development, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, 53705, USA
- Department of Chemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Weiping Tang
- Lachman Institute of Pharmaceutical Development, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, 53705, USA.
- Department of Chemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA.
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22
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Pączek S, Zajkowska M, Mroczko B. Pigment Epithelial-Derived Factor in Pancreatic and Liver Cancers-From Inflammation to Cancer. Biomedicines 2024; 12:2260. [PMID: 39457573 PMCID: PMC11504982 DOI: 10.3390/biomedicines12102260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 09/28/2024] [Accepted: 10/03/2024] [Indexed: 10/28/2024] Open
Abstract
Gastrointestinal (GI) cancers are among the leading causes of mortality worldwide. Despite the emergence of new possibilities that offer hope regarding the successful treatment of these cancers, they still represent a significant global health burden. These cancers can arise from various cell types within the gastrointestinal tract and may exhibit different characteristics, behaviors, and treatment approaches. Both the prognosis and the outcomes of GI treatment remain problematic because these tumors are primarily diagnosed in advanced clinical stages. Current biomarkers exhibit limited sensitivity and specificity. Therefore, when developing strategies for the diagnosis and treatment of GI cancers, it is of fundamental importance to discover new biomarkers capable of addressing the challenges of early-stage diagnosis and the presence of lymph node metastases. Pigment epithelial-derived factor (PEDF) has garnered interest due to its inhibitory effects on the migration and proliferation of cancer cells. This protein has been suggested to be involved in various inflammation-related diseases, including cancer, through various mechanisms. It was also observed that reducing the level of PEDF is sufficient to trigger an inflammatory response. This suggests that PEDF is an endogenous anti-inflammatory factor. Overall, PEDF is a versatile protein with diverse biological functions that span across different tissues and organ systems. Its multifaceted activities make it an intriguing target for therapeutic interventions in various diseases, including cancer, neurodegeneration, and metabolic disorders. This review, for the first time, summarizes the role of PEDF in the pathogenesis of selected GI cancers and its potential utility in early diagnosis, prognosis, and therapeutic strategies for this malignancy.
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Affiliation(s)
- Sara Pączek
- Department of Biochemical Diagnostics, University Hospital in Białystok, 15-269 Białystok, Poland; (S.P.); (B.M.)
| | - Monika Zajkowska
- Department of Biochemical Diagnostics, University Hospital in Białystok, 15-269 Białystok, Poland; (S.P.); (B.M.)
- Department of Neurodegeneration Diagnostics, Medical University of Białystok, 15 A, Waszyngtona St., 15-269 Białystok, Poland
| | - Barbara Mroczko
- Department of Biochemical Diagnostics, University Hospital in Białystok, 15-269 Białystok, Poland; (S.P.); (B.M.)
- Department of Neurodegeneration Diagnostics, Medical University of Białystok, 15 A, Waszyngtona St., 15-269 Białystok, Poland
- Department of Biochemical Diagnostics, Medical University of Białystok, 15-089 Białystok, Poland
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23
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Yonk MG, Lim MA, Thompson CM, Tora MS, Lakhina Y, Du Y, Hoang KB, Molinaro AM, Boulis NM, Hassaneen W, Lei K. Improving glioma drug delivery: A multifaceted approach for glioma drug development. Pharmacol Res 2024; 208:107390. [PMID: 39233056 PMCID: PMC11440560 DOI: 10.1016/j.phrs.2024.107390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Revised: 08/16/2024] [Accepted: 08/28/2024] [Indexed: 09/06/2024]
Abstract
Glioma is one of the most common central nervous system (CNS) cancers that can be found within the brain and the spinal cord. One of the pressing issues plaguing the development of therapeutics for glioma originates from the selective and semipermeable CNS membranes: the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB). It is difficult to bypass these membranes and target the desired cancerous tissue because the purpose of the BBB and BSCB is to filter toxins and foreign material from invading CNS spaces. There are currently four varieties of Food and Drug Administration (FDA)-approved drug treatment for glioma; yet these therapies have limitations including, but not limited to, relatively low transmission through the BBB/BSCB, despite pharmacokinetic characteristics that allow them to cross the barriers. Steps must be taken to improve the development of novel and repurposed glioma treatments through the consideration of pharmacological profiles and innovative drug delivery techniques. This review addresses current FDA-approved glioma treatments' gaps, shortcomings, and challenges. We then outline how incorporating computational BBB/BSCB models and innovative drug delivery mechanisms will help motivate clinical advancements in glioma drug delivery. Ultimately, considering these attributes will improve the process of novel and repurposed drug development in glioma and the efficacy of glioma treatment.
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Affiliation(s)
- Marybeth G Yonk
- Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, USA; College of Sciences, Georgia Institute of Technology, Atlanta, GA, USA
| | - Megan A Lim
- Carle Illinois College of Medicine, University of Illinois Urbana Champaign, Champaign, IL, USA; Department of Neurosurgery, Carle Foundation Hospital, Urbana, IL, USA
| | - Charee M Thompson
- Carle Illinois College of Medicine, University of Illinois Urbana Champaign, Champaign, IL, USA; College of Liberal Arts & Sciences, University of Illinois Urbana Champaign, Champaign, IL, USA
| | - Muhibullah S Tora
- Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, USA; Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - Yuliya Lakhina
- Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, USA
| | - Yuhong Du
- Department of Pharmacology and Chemical Biology Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Kimberly B Hoang
- Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, USA
| | - Annette M Molinaro
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Nicholas M Boulis
- Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, USA; Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - Wael Hassaneen
- Carle Illinois College of Medicine, University of Illinois Urbana Champaign, Champaign, IL, USA; Department of Neurosurgery, Carle Foundation Hospital, Urbana, IL, USA.
| | - Kecheng Lei
- Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, USA.
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24
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Gaudio G, Martino E, Pellizzari G, Cavallone M, Castellano G, Omar A, Katselashvili L, Trapani D, Curigliano G. Developing combination therapies with biologics in triple-negative breast cancer. Expert Opin Biol Ther 2024; 24:1075-1094. [PMID: 39360776 DOI: 10.1080/14712598.2024.2408756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Accepted: 09/22/2024] [Indexed: 10/11/2024]
Abstract
INTRODUCTION Novel compounds have entered the triple-negative breast cancer (TNBC) treatment algorithm, namely immune checkpoints inhibitors (ICIs), PARP inhibitors and antibody-drug conjugates (ADCs). The optimization of treatment efficacy can be enhanced with the use of combination treatments, and the incorporation of novel compounds. In this review, we discuss the combination treatments under development for the treatment of TNBC. AREAS COVERED The development of new drugs occurring in recent years has boosted the research for novel combinations to target TNBC heterogeneity and improve outcomes. ICIs, ADCs, tyrosine kinase inhibitors (TKIs), and PARP inhibitors have emerged as leading players in this new landscape, while other compounds like novel intracellular pathways inhibitors or cancer vaccines are drawing more and more interest. The future of TNBC is outlined in combination approaches, and based on new cancer targets, including many chemotherapy-free treatments. EXPERT OPINION A large number of TNBC therapies have either proved clinically ineffective or weighted by unacceptable safety profiles. Others, however, have provided promising results and are currently in late-stage clinical trials, while a few have actually changed clinical practice in recent years. As novel, more and more selective drugs come up, combination strategies focusing the concept of synergy are fully warranted for the future.
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Affiliation(s)
- Gilda Gaudio
- Department of Radiological, Oncological and Pathological Science, Sapienza University of Rome, Rome, Italy
- Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
| | - Enzo Martino
- Department of Radiological, Oncological and Pathological Science, Sapienza University of Rome, Rome, Italy
- Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
| | - Gloria Pellizzari
- Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Haemato-Oncology (DIPO), University of Milan, Milan, Italy
| | - Matteo Cavallone
- Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Haemato-Oncology (DIPO), University of Milan, Milan, Italy
| | - Grazia Castellano
- Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Haemato-Oncology (DIPO), University of Milan, Milan, Italy
| | - Abeid Omar
- Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Nuclear Medicine, Kenyatta University Teaching Referral and Research Hospital, Nairobi, Kenya
| | - Lika Katselashvili
- Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology, Caucasus Medical Centre, Tbilisi, Georgia
| | - Dario Trapani
- Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Haemato-Oncology (DIPO), University of Milan, Milan, Italy
| | - Giuseppe Curigliano
- Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Haemato-Oncology (DIPO), University of Milan, Milan, Italy
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25
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Basheeruddin M, Qausain S. Hypoxia-Inducible Factor 1-Alpha (HIF-1α) and Cancer: Mechanisms of Tumor Hypoxia and Therapeutic Targeting. Cureus 2024; 16:e70700. [PMID: 39493156 PMCID: PMC11529905 DOI: 10.7759/cureus.70700] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 10/02/2024] [Indexed: 11/05/2024] Open
Abstract
Hypoxia-inducible factor 1-alpha (HIF-1α) is necessary for cells to adapt to low oxygen levels often present in the tumor microenvironment. HIF-1α triggers a transcriptional program that promotes invasion, angiogenesis, metabolic reprogramming, and cell survival when it is active in hypoxic environments. These processes together lead to the growth and spread of tumors. This review article examines the molecular mechanisms by which HIF-1α contributes to tumor progression, including its regulation by oxygen-dependent and independent pathways, interactions with oncogenic signaling networks, and impact on the tumor microenvironment. Additionally, we explore current therapeutic strategies targeting HIF-1α, such as small molecule inhibitors, RNA interference, and immunotherapy approaches. Understanding the multifaceted roles of HIF-1α in cancer biology not only elucidates the complexities of tumor hypoxia but also opens avenues for developing novel and more effective cancer therapies.
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Affiliation(s)
- Mohd Basheeruddin
- Biochemistry, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Sana Qausain
- Biochemistry, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
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26
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Jain M, Crites MK, Rich P, Bajantri B. Malignant Pleural Mesothelioma: A Comprehensive Review. J Clin Med 2024; 13:5837. [PMID: 39407894 PMCID: PMC11476893 DOI: 10.3390/jcm13195837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 09/27/2024] [Accepted: 09/27/2024] [Indexed: 10/20/2024] Open
Abstract
Mesotheliomas are hyperplastic tumors that envelop the serosal membranes that safeguard the body's external surfaces. Although certain instances may exhibit indolent characteristics, a significant number of tumors demonstrate rapid progression and a poor prognosis. Mesotheliomas are typically categorized as benign or malignant, with malignant mesothelioma being more frequently linked to asbestos exposure. Malignant pleural mesothelioma (MPM) predominantly impacts males and often emerges in the late 50 s or beyond, characterized by a median age of early 70 s among patients exposed to asbestos lasting from 2 to 4 decades. Respiratory exposure to asbestos particles leads to the development of malignant mesothelioma, characterized by recurrent inflammation, disruption of cell division, activation of proto-oncogenes, and generation of free radicals. In pleural mesothelioma, BAP1, CDKN2A, and NF are the most often mutated genes. Accurate diagnosis and assessment usually require the use of chest computed tomography (CT) scans, magnetic resonance imaging (MRI), and positron emission tomography (PET). Radiation therapy, immunotherapy, chemotherapy, and surgery are some of the treatment options that are currently available. This systematic review provides a comprehensive analysis of the latest research, biomarkers, evaluation, and management strategies for malignant pleural mesothelioma.
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Affiliation(s)
- Molly Jain
- Parkview Health, Fort Wayne, IN 46845, USA (P.R.)
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27
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Sriramulu S, Thoidingjam S, Speers C, Nyati S. Present and Future of Immunotherapy for Triple-Negative Breast Cancer. Cancers (Basel) 2024; 16:3250. [PMID: 39409871 PMCID: PMC11475478 DOI: 10.3390/cancers16193250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 09/18/2024] [Accepted: 09/23/2024] [Indexed: 10/20/2024] Open
Abstract
Triple-negative breast cancer (TNBC) lacks the expression of estrogen receptors (ERs), human epidermal growth factor receptor 2 (HER2), and progesterone receptors (PRs). TNBC has the poorest prognosis among breast cancer subtypes and is more likely to respond to immunotherapy due to its higher expression of PD-L1 and a greater percentage of tumor-infiltrating lymphocytes. Immunotherapy has revolutionized TNBC treatment, especially with the FDA's approval of pembrolizumab (Keytruda) combined with chemotherapy for advanced cases, opening new avenues for treating this deadly disease. Although immunotherapy can significantly improve patient outcomes in a subset of patients, achieving the desired response rate for all remains an unmet clinical goal. Strategies that enhance responses to immune checkpoint blockade, including combining immunotherapy with chemotherapy, molecularly targeted therapy, or radiotherapy, may improve response rates and clinical outcomes. In this review, we provide a short background on TNBC and immunotherapy and explore the different types of immunotherapy strategies that are currently being evaluated in TNBC. Additionally, we review why combination strategies may be beneficial, provide an overview of the combination strategies, and discuss the novel immunotherapeutic opportunities that may be approved in the near future for TNBC.
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Affiliation(s)
- Sushmitha Sriramulu
- Department of Radiation Oncology, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI 48202, USA
| | - Shivani Thoidingjam
- Department of Radiation Oncology, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI 48202, USA
| | - Corey Speers
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Radiation Oncology, UH Seidman Cancer Center, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Shyam Nyati
- Department of Radiation Oncology, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI 48202, USA
- Henry Ford Health + Michigan State University Health Sciences, Detroit, MI 48202, USA
- Department of Radiology, Michigan State University, East Lansing, MI 48824, USA
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28
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Oghalaie A, Hosseini ME, Hosseininejad-Chafi M, Eftekhari Z, Behdani M, Kazemi-Lomedasht F. Advances in immunotoxin engineering: precision therapeutic strategies in modern oncology. Med Oncol 2024; 41:239. [PMID: 39230639 DOI: 10.1007/s12032-024-02478-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/12/2024] [Indexed: 09/05/2024]
Abstract
Immunotoxins (ITs) are specialized therapeutic agents designed for targeted treatment, particularly in cancer therapy. They consist of a monoclonal antibody or antibody fragment linked to a potent cytotoxic agent, such as bacterial- or plant-derived toxins like diphtheria toxin, ricin, or pseudomonas exotoxin. The monoclonal antibody component specifically binds to antigens expressed on the surface of target cells, facilitating the internalization of the IT. Once inside the cell, the cytotoxic agent is released, disrupting essential cellular processes and leading to cell death. This targeted approach minimizes damage to healthy tissues while effectively eliminating diseased cells. The production of ITs involves two primary methods: recombinant fusion and chemical conjugation. In recombinant fusion, genetic engineering is used to create a fusion protein that combines the antibody and toxin, ensuring precise control over their ratio and functionality. In chemical conjugation, pre-existing antibodies are chemically linked to toxins, allowing for greater flexibility in combining different antibodies and cytotoxic agents. Each method has its advantages and challenges, influencing the specificity, production complexity, and therapeutic potential of the resulting ITs. As research advances, ITs continue to show promise not only in oncology but also in treating other diseases, including inflammatory conditions and atherosclerosis. The precise targeting and potent effects of ITs make them a valuable tool in the development of new therapeutic strategies.
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Affiliation(s)
- Akbar Oghalaie
- Venom and Biotherapeutics Molecules Laboratory, Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Mahmoud Eshagh Hosseini
- Gastroenterology and Liver Department, Amiralam Hospital, University of Medical Sciences, Tehran, Iran
| | - Mohammad Hosseininejad-Chafi
- Venom and Biotherapeutics Molecules Laboratory, Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Zohre Eftekhari
- Venom and Biotherapeutics Molecules Laboratory, Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Mahdi Behdani
- Venom and Biotherapeutics Molecules Laboratory, Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Fatemeh Kazemi-Lomedasht
- Venom and Biotherapeutics Molecules Laboratory, Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
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29
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Prome AA, Robin TB, Ahmed N, Rani NA, Ahmad I, Patel H, Bappy MNI, Zinnah KMA. A reverse docking approach to explore the anticancer potency of natural compounds by interfering metastasis and angiogenesis. J Biomol Struct Dyn 2024; 42:7174-7189. [PMID: 37526218 DOI: 10.1080/07391102.2023.2240895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 07/14/2023] [Indexed: 08/02/2023]
Abstract
Angiogenesis, which results in the formation of new blood and lymph vessels, is required to serve metastatic cancer progression. Cancer medications may target these two interconnected pathways. Phytocompounds have emerged as promising options for treating cancer. In this study, we used a reverse docking strategy to find new candidate molecules for cancer treatment that target both pathways. Following a literature study, the important cancer-causing proteins vascular endothelial growth factor D (VEGF-D) and basic fibroblast growth factor (bFGF) for angiogenesis and matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) for the metastatic pathway were targeted. Protein Data Bank was used to retrieve the structures of chosen proteins. 22 significant plant metabolites were identified as having anticancer activity. To determine the important protein binding residues, active site prediction was used. Using Lenvatinib and Withaferin A as reference ligands, the binding affinity of certain proteins for plant metabolites was determined by docking analysis. Homoharringtonine and viniferin, both have higher binding affinities when compared to reference ligands, with docking scores of -180.96 and -180.36 against the protein MMP-9, respectively. Moreover, Viniferin showed the highest binding affinity with both MMP-9 and MMP-2 proteins, which were then subjected to a 100-ns molecular dynamic simulation. where they were found to be significantly stable. In pharmacoinformatics investigations, the majority of our compounds were found to be non-toxic for the host. In this study, we suggested natural substances as cutting-edge anticancer treatments that target both angiogenesis and metastasis, which may aid in accelerating drug development and identifying viable therapeutic candidates.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Anindita Ash Prome
- Faculty of Biotechnology and Genetic Engineering, Sylhet Agricultural University, Sylhet, Bangladesh
| | - Tanjin Barketullah Robin
- Faculty of Biotechnology and Genetic Engineering, Sylhet Agricultural University, Sylhet, Bangladesh
| | - Nadim Ahmed
- Faculty of Biotechnology and Genetic Engineering, Sylhet Agricultural University, Sylhet, Bangladesh
| | - Nurul Amin Rani
- Faculty of Biotechnology and Genetic Engineering, Sylhet Agricultural University, Sylhet, Bangladesh
| | - Iqrar Ahmad
- Department of Pharmaceutical Chemistry, Prof. Ravindra Nikam College of Pharmacy, Dhule, Maharashtra, India
| | - Harun Patel
- Division of Computer Aided Drug Design, Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, India
| | - Md Nazmul Islam Bappy
- Faculty of Biotechnology and Genetic Engineering, Sylhet Agricultural University, Sylhet, Bangladesh
- Department of Animal and Fish Biotechnology, Sylhet Agricultural University, Sylhet, Bangladesh
| | - Kazi Md Ali Zinnah
- Faculty of Biotechnology and Genetic Engineering, Sylhet Agricultural University, Sylhet, Bangladesh
- Department of Animal and Fish Biotechnology, Sylhet Agricultural University, Sylhet, Bangladesh
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Dumitru CS, Raica M. A Splice Form of VEGF, a Potential Anti-Angiogenetic Form of Head and Neck Squamous Cell Cancer Inhibition. Int J Mol Sci 2024; 25:8855. [PMID: 39201541 PMCID: PMC11354464 DOI: 10.3390/ijms25168855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Revised: 08/10/2024] [Accepted: 08/13/2024] [Indexed: 09/02/2024] Open
Abstract
Angiogenesis, primarily mediated by vascular endothelial growth factor (VEGF), is a fundamental step in the progression and metastasis of head and neck squamous cell carcinoma (HNSCC). Traditional anti-angiogenic therapies that target the VEGF pathway have shown promise but are often associated with significant side effects and variable efficacy due to the complexity of the angiogenic signaling pathway. This review highlights the potential of a specific VEGF splice form, VEGF165b, as an innovative therapeutic target for HNSCC. VEGF165b, unlike standard VEGF, is a natural inhibitor that binds to VEGF receptors without triggering pro-angiogenic signaling. Its distinct molecular structure and behavior suggest ways to modulate angiogenesis. This concept is particularly relevant when studying HNSCC, as introducing VEGF165b's anti-angiogenic properties offers a novel approach to understanding and potentially influencing the disease's dynamics. The review synthesizes experimental evidence suggesting the efficacy of VEGF165b in inhibiting tumor-induced angiogenesis and provides insight into a novel therapeutic strategy that could better manage HNSCC by selectively targeting aberrant vascular growth. This approach not only provides a potential pathway for more targeted and effective treatment options but also opens the door to a new paradigm in anti-angiogenic therapy with the possibility of reduced systemic toxicity. Our investigation is reshaping the future of HNSCC treatment by setting the stage for future research on VEGF splice variants as a tool for personalized medicine.
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Affiliation(s)
- Cristina Stefania Dumitru
- Department of Microscopic Morphology/Histology, Angiogenesis Research Center, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania;
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Pan X, Li X, Dong L, Liu T, Zhang M, Zhang L, Zhang X, Huang L, Shi W, Sun H, Fang Z, Sun J, Huang Y, Shao H, Wang Y, Yin M. Tumour vasculature at single-cell resolution. Nature 2024; 632:429-436. [PMID: 38987599 DOI: 10.1038/s41586-024-07698-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 06/10/2024] [Indexed: 07/12/2024]
Abstract
Tumours can obtain nutrients and oxygen required to progress and metastasize through the blood supply1. Inducing angiogenesis involves the sprouting of established vessel beds and their maturation into an organized network2,3. Here we generate a comprehensive atlas of tumour vasculature at single-cell resolution, encompassing approximately 200,000 cells from 372 donors representing 31 cancer types. Trajectory inference suggested that tumour angiogenesis was initiated from venous endothelial cells and extended towards arterial endothelial cells. As neovascularization elongates (through angiogenic stages SI, SII and SIII), APLN+ tip cells at the SI stage (APLN+ TipSI) advanced to TipSIII cells with increased Notch signalling. Meanwhile, stalk cells, following tip cells, transitioned from high chemokine expression to elevated TEK (also known as Tie2) expression. Moreover, APLN+ TipSI cells not only were associated with disease progression and poor prognosis but also hold promise for predicting response to anti-VEGF therapy. Lymphatic endothelial cells demonstrated two distinct differentiation lineages: one responsible for lymphangiogenesis and the other involved in antigen presentation. In pericytes, endoplasmic reticulum stress was associated with the proangiogenic BASP1+ matrix-producing pericytes. Furthermore, intercellular communication analysis showed that neovascular endothelial cells could shape an immunosuppressive microenvironment conducive to angiogenesis. This study depicts the complexity of tumour vasculature and has potential clinical significance for anti-angiogenic therapy.
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Affiliation(s)
- Xu Pan
- Clinical Research Center (CRC), Medical Pathology Center (MPC), Cancer Early Detection and Treatment Center (CEDTC) and Translational Medicine Research Center (TMRC), Chongqing University Three Gorges Hospital, Chongqing University, Chongqing, China
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Xin Li
- Clinical Research Center (CRC), Medical Pathology Center (MPC), Cancer Early Detection and Treatment Center (CEDTC) and Translational Medicine Research Center (TMRC), Chongqing University Three Gorges Hospital, Chongqing University, Chongqing, China
- Chongqing Technical Innovation Center for Quality Evaluation and Identification of Authentic Medicinal Herbs, Chongqing, China
- School of Medicine, Chongqing University, Chongqing, China
| | - Liang Dong
- Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China
| | - Teng Liu
- Clinical Research Center (CRC), Medical Pathology Center (MPC), Cancer Early Detection and Treatment Center (CEDTC) and Translational Medicine Research Center (TMRC), Chongqing University Three Gorges Hospital, Chongqing University, Chongqing, China
- Chongqing Technical Innovation Center for Quality Evaluation and Identification of Authentic Medicinal Herbs, Chongqing, China
- School of Medicine, Chongqing University, Chongqing, China
| | - Min Zhang
- Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China
| | - Lining Zhang
- Clinical Research Center (CRC), Medical Pathology Center (MPC), Cancer Early Detection and Treatment Center (CEDTC) and Translational Medicine Research Center (TMRC), Chongqing University Three Gorges Hospital, Chongqing University, Chongqing, China
- Chongqing Technical Innovation Center for Quality Evaluation and Identification of Authentic Medicinal Herbs, Chongqing, China
- School of Medicine, Chongqing University, Chongqing, China
| | - Xiyuan Zhang
- Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China
| | - Lingjuan Huang
- Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China
| | - Wensheng Shi
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
| | - Hongyin Sun
- Clinical Research Center (CRC), Medical Pathology Center (MPC), Cancer Early Detection and Treatment Center (CEDTC) and Translational Medicine Research Center (TMRC), Chongqing University Three Gorges Hospital, Chongqing University, Chongqing, China
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Zhaoyu Fang
- Hunan Provincial Key Lab on Bioinformatics, School of Computer Science and Engineering at Central South University, Changsha, China
| | - Jie Sun
- Clinical Research Center (CRC), Medical Pathology Center (MPC), Cancer Early Detection and Treatment Center (CEDTC) and Translational Medicine Research Center (TMRC), Chongqing University Three Gorges Hospital, Chongqing University, Chongqing, China
- Chongqing Technical Innovation Center for Quality Evaluation and Identification of Authentic Medicinal Herbs, Chongqing, China
- School of Medicine, Chongqing University, Chongqing, China
| | - Yaoxuan Huang
- Clinical Research Center (CRC), Medical Pathology Center (MPC), Cancer Early Detection and Treatment Center (CEDTC) and Translational Medicine Research Center (TMRC), Chongqing University Three Gorges Hospital, Chongqing University, Chongqing, China
- Chongqing Technical Innovation Center for Quality Evaluation and Identification of Authentic Medicinal Herbs, Chongqing, China
- School of Medicine, Chongqing University, Chongqing, China
| | - Hua Shao
- Clinical Research Center (CRC), Medical Pathology Center (MPC), Cancer Early Detection and Treatment Center (CEDTC) and Translational Medicine Research Center (TMRC), Chongqing University Three Gorges Hospital, Chongqing University, Chongqing, China
- Chongqing Technical Innovation Center for Quality Evaluation and Identification of Authentic Medicinal Herbs, Chongqing, China
- School of Medicine, Chongqing University, Chongqing, China
| | - Yeqi Wang
- Key Laboratory for Biorheological Science and Technology of Ministry of Education, Bioengineering College of Chongqing University, Chongqing, China
| | - Mingzhu Yin
- Clinical Research Center (CRC), Medical Pathology Center (MPC), Cancer Early Detection and Treatment Center (CEDTC) and Translational Medicine Research Center (TMRC), Chongqing University Three Gorges Hospital, Chongqing University, Chongqing, China.
- Chongqing Technical Innovation Center for Quality Evaluation and Identification of Authentic Medicinal Herbs, Chongqing, China.
- School of Medicine, Chongqing University, Chongqing, China.
- Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China.
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Leong SP, Witte MH. Cancer metastasis through the lymphatic versus blood vessels. Clin Exp Metastasis 2024; 41:387-402. [PMID: 38940900 PMCID: PMC11374872 DOI: 10.1007/s10585-024-10288-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 04/10/2024] [Indexed: 06/29/2024]
Abstract
Whether cancer cells metastasize from the primary site to the distant sites via the lymphatic vessels or the blood vessels directly into the circulation is still under intense study. In this review article, we follow the journey of cancer cells metastasizing to the sentinel lymph nodes and beyond to the distant sites. We emphasize cancer heterogeneity and microenvironment as major determinants of cancer metastasis. Multiple molecules have been found to be associated with the complicated process of metastasis. Based on the large sentinel lymph node data, it is reasonable to conclude that cancer cells may metastasize through the blood vessels in some cases but in most cases, they use the sentinel lymph nodes as the major gateway to enter the circulation to distant sites.
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Affiliation(s)
- Stanley P Leong
- California Pacific Medical Center and Research Institute, University of California School of Medicine, San Francisco, USA.
| | - Marlys H Witte
- Department of Surgery, Neurosurgery and Pediatrics, University of Arizona College of Medicine-Tucson, Tucson, AZ, USA
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Trivedi AH, Wang VZ, McClain EJ, Vyas PS, Swink IR, Snell ED, Cheng BC, DeMeo PJ. The Categorization of Perinatal Derivatives for Orthopedic Applications. Biomedicines 2024; 12:1544. [PMID: 39062117 PMCID: PMC11274709 DOI: 10.3390/biomedicines12071544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 07/01/2024] [Accepted: 07/09/2024] [Indexed: 07/28/2024] Open
Abstract
Musculoskeletal (MSK) pathology encompasses an array of conditions that can cause anything from mild discomfort to permanent injury. Their prevalence and impact on disability have sparked interest in more effective treatments, particularly within orthopedics. As a result, the human placenta has come into focus within regenerative medicine as a perinatal derivative (PnD). These biologics are sourced from components of the placenta, each possessing a unique composition of collagens, proteins, and factors believed to aid in healing and regeneration. This review aims to explore the current literature on PnD biologics and their potential benefits for treating various MSK pathologies. We delve into different types of PnDs and their healing effects on muscles, tendons, bones, cartilage, ligaments, and nerves. Our discussions highlight the crucial role of immune modulation in the healing process for each condition. PnDs have been observed to influence the balance between anti- and pro-inflammatory factors and, in some cases, act as biologic scaffolds for tissue growth. Additionally, we assess the range of PnDs available, while also addressing gaps in our understanding, particularly regarding biologic processing methods. Although certain PnD biologics have varying levels of support in orthopedic literature, further clinical investigations are necessary to fully evaluate their impact on human patients.
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Affiliation(s)
- Amol H. Trivedi
- Orthopaedic Institute, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA 15212, USA; (A.H.T.); (V.Z.W.); (E.J.M.IV); (P.S.V.); (I.R.S.); (E.D.S.); (P.J.D.)
- Drexel University College of Medicine, Drexel University, University City Campus, Philadelphia, PA 19104, USA
| | - Vicki Z. Wang
- Orthopaedic Institute, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA 15212, USA; (A.H.T.); (V.Z.W.); (E.J.M.IV); (P.S.V.); (I.R.S.); (E.D.S.); (P.J.D.)
| | - Edward J. McClain
- Orthopaedic Institute, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA 15212, USA; (A.H.T.); (V.Z.W.); (E.J.M.IV); (P.S.V.); (I.R.S.); (E.D.S.); (P.J.D.)
| | - Praveer S. Vyas
- Orthopaedic Institute, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA 15212, USA; (A.H.T.); (V.Z.W.); (E.J.M.IV); (P.S.V.); (I.R.S.); (E.D.S.); (P.J.D.)
| | - Isaac R. Swink
- Orthopaedic Institute, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA 15212, USA; (A.H.T.); (V.Z.W.); (E.J.M.IV); (P.S.V.); (I.R.S.); (E.D.S.); (P.J.D.)
| | - Edward D. Snell
- Orthopaedic Institute, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA 15212, USA; (A.H.T.); (V.Z.W.); (E.J.M.IV); (P.S.V.); (I.R.S.); (E.D.S.); (P.J.D.)
| | - Boyle C. Cheng
- Orthopaedic Institute, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA 15212, USA; (A.H.T.); (V.Z.W.); (E.J.M.IV); (P.S.V.); (I.R.S.); (E.D.S.); (P.J.D.)
| | - Patrick J. DeMeo
- Orthopaedic Institute, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA 15212, USA; (A.H.T.); (V.Z.W.); (E.J.M.IV); (P.S.V.); (I.R.S.); (E.D.S.); (P.J.D.)
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Kang YK, Ryu MH, Hong YS, Choi CM, Kim TW, Ryoo BY, Kim JE, Weis JR, Kingsford R, Park CH, Jang S, McGinn A, Werner TL, Sharma S. Phase 1/2a Study of Rivoceranib, a Selective VEGFR-2 Angiogenesis Inhibitor, in Patients with Advanced Solid Tumors. Cancer Res Treat 2024; 56:743-750. [PMID: 38271925 PMCID: PMC11261186 DOI: 10.4143/crt.2023.980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 01/17/2024] [Indexed: 01/27/2024] Open
Abstract
PURPOSE This study aimed to report the results from an early-phase study of rivoceranib, an oral tyrosine kinase inhibitor highly selective for vascular endothelial growth factor receptor 2, in patients with advanced solid tumors. MATERIALS AND METHODS In this open-label, single-arm, dose-escalating, multicenter three-part phase 1/2a trial, patients had advanced solid tumors refractory to conventional therapy. Part 1 evaluated the safety and pharmacokinetics of five ascending once-daily doses of rivoceranib from 81 mg to 685 mg. Part 2 evaluated the safety and antitumor activity of once-daily rivoceranib 685 mg. Part 3 was conducted later, due to lack of maximum tolerated dose determination in part 1, to evaluate the safety and preliminary efficacy of once-daily rivoceranib 805 mg in patients with unresectable or advanced gastric cancer. RESULTS A total of 61 patients were enrolled in parts 1 (n=25), 2 (n=30), and 3 (n=6). In parts 1 and 2, patients were white (45.5%) or Asian (54.5%), and 65.6% were male. The most common grade ≥ 3 adverse events were hypertension (32.7%), hyponatremia (10.9%), and hypophosphatemia (10.9%). The objective response rate (ORR) was 15.2%. In part 3, dose-limiting toxicities occurred in two out of six patients: grade 3 febrile neutropenia decreased appetite, and fatigue. The ORR was 33%. CONCLUSION The recommended phase 2 dose of rivoceranib was determined to be 685 mg once daily, which showed adequate efficacy with a manageable safety profile (NCT01497704 and NCT02711969).
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Affiliation(s)
- Yoon-Koo Kang
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Min-Hee Ryu
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Yong Sang Hong
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chang-Min Choi
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Tae Won Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Baek-Yeol Ryoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jeong Eun Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - John R. Weis
- University of Utah and Huntsman Cancer Institute, Salt Lake City, UT, USA
| | - Rachel Kingsford
- University of Utah and Huntsman Cancer Institute, Salt Lake City, UT, USA
| | | | | | | | - Theresa L. Werner
- University of Utah and Huntsman Cancer Institute, Salt Lake City, UT, USA
| | - Sunil Sharma
- Translational Genomics Research Institute, Phoenix, AZ, USA
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Garlisi B, Lauks S, Aitken C, Ogilvie LM, Lockington C, Petrik D, Eichhorn JS, Petrik J. The Complex Tumor Microenvironment in Ovarian Cancer: Therapeutic Challenges and Opportunities. Curr Oncol 2024; 31:3826-3844. [PMID: 39057155 PMCID: PMC11275383 DOI: 10.3390/curroncol31070283] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 06/27/2024] [Accepted: 06/28/2024] [Indexed: 07/28/2024] Open
Abstract
The tumor microenvironment (TME) in ovarian cancer (OC) has much greater complexity than previously understood. In response to aggressive pro-angiogenic stimulus, blood vessels form rapidly and are dysfunctional, resulting in poor perfusion, tissue hypoxia, and leakiness, which leads to increased interstitial fluid pressure (IFP). Decreased perfusion and high IFP significantly inhibit the uptake of therapies into the tumor. Within the TME, there are numerous inhibitor cells, such as myeloid-derived suppressor cells (MDSCs), tumor association macrophages (TAMs), regulatory T cells (Tregs), and cancer-associated fibroblasts (CAFs) that secrete high numbers of immunosuppressive cytokines. This immunosuppressive environment is thought to contribute to the lack of success of immunotherapies such as immune checkpoint inhibitor (ICI) treatment. This review discusses the components of the TME in OC, how these characteristics impede therapeutic efficacy, and some strategies to alleviate this inhibition.
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Affiliation(s)
| | | | | | | | | | | | | | - Jim Petrik
- Department of Biomedical Sciences, University of Guelph, Guelph, ON N1G 2W1, Canada; (B.G.); (S.L.); (C.A.); (L.M.O.); (C.L.); (D.P.); (J.S.E.)
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Singh R, Chandi SK, Sran S, Aulakh SK, Nijjar GS, Singh K, Singh S, Tanvir F, Kaur Y, Sandhu APS. Emerging Therapeutic Strategies in Cardiovascular Diseases. Cureus 2024; 16:e64388. [PMID: 39131016 PMCID: PMC11317025 DOI: 10.7759/cureus.64388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/12/2024] [Indexed: 08/13/2024] Open
Abstract
Cardiovascular diseases (CVDs), including ischemic heart disease and stroke, are the leading cause of mortality worldwide, causing nearly 20 million deaths annually. Traditional therapies, while effective, have not curbed the rising prevalence of CVDs driven by aging populations and lifestyle factors. This review highlights innovative therapeutic strategies that show promise in improving patient outcomes and transforming cardiovascular care. Emerging pharmacological treatments, such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and sodium-glucose co-transporter 2 (SGLT2) inhibitors, introduce novel mechanisms to complement existing therapies, significantly reducing cardiovascular events and mortality. These advancements emphasize the necessity of ongoing clinical trials and research to discover new therapeutic targets. Advanced biological therapies, including gene therapy, stem cell therapy, and RNA-based treatments, offer groundbreaking potential for repairing and regenerating damaged cardiovascular tissues. Despite being in various stages of clinical validation, early results are promising, suggesting these therapies could fundamentally change the CVD treatment landscape. Innovative medical devices and technologies, such as implantable devices, minimally invasive procedures, and wearable technology, are revolutionizing CVD management. These advancements facilitate early diagnosis, continuous monitoring, and effective treatment, driving care out of hospitals and into homes, improving patient outcomes and reducing healthcare costs. Personalized medicine, driven by genetic profiling and biomarker identification, allows for tailored therapies that enhance treatment efficacy and minimize adverse effects. However, the adoption of these emerging therapies faces significant challenges, including regulatory hurdles, cost and accessibility issues, and ethical considerations. Addressing these barriers and fostering interdisciplinary collaboration are crucial for accelerating the development and implementation of innovative treatments. Integrating emerging therapeutic strategies in cardiovascular care holds immense potential to transform CVD management. By prioritizing future research and overcoming existing challenges, a new era of personalized, effective, and accessible cardiovascular care can be achieved.
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Affiliation(s)
- Rajinderpal Singh
- Internal Medicine, Government Medical College Amritsar, Amritsar, IND
| | | | - Seerat Sran
- Internal Medicine, Sri Guru Ram Das University of Health Sciences and Research, Amritsar, IND
| | - Smriti K Aulakh
- Internal Medicine, Sri Guru Ram Das University of Health Sciences and Research, Amritsar, IND
| | | | | | - Sumerjit Singh
- Medicine, Government Medical College Amritsar, Amritsar, IND
| | - Fnu Tanvir
- Medicine, Government Medical College Amritsar, Amritsar, IND
| | - Yasmeen Kaur
- Medicine, Government Medical College Amritsar, Amritsar, IND
| | - Ajay Pal Singh Sandhu
- Medicine, Sri Guru Ram Das University of Health Sciences and Research, Amritsar, IND
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Amin N, Abbasi IN, Wu F, Shi Z, Sundus J, Badry A, Yuan X, Zhao BX, Pan J, Mi XD, Luo Y, Geng Y, Fang M. The Janus face of HIF-1α in ischemic stroke and the possible associated pathways. Neurochem Int 2024; 177:105747. [PMID: 38657682 DOI: 10.1016/j.neuint.2024.105747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 03/01/2024] [Accepted: 04/19/2024] [Indexed: 04/26/2024]
Abstract
Stroke is the most devastating disease, causing paralysis and eventually death. Many clinical and experimental trials have been done in search of a new safe and efficient medicine; nevertheless, scientists have yet to discover successful remedies that are also free of adverse effects. This is owing to the variability in intensity, localization, medication routes, and each patient's immune system reaction. HIF-1α represents the modern tool employed to treat stroke diseases due to its functions: downstream genes such as glucose metabolism, angiogenesis, erythropoiesis, and cell survival. Its role can be achieved via two downstream EPO and VEGF strongly related to apoptosis and antioxidant processes. Recently, scientists paid more attention to drugs dealing with the HIF-1 pathway. This review focuses on medicines used for ischemia treatment and their potential HIF-1α pathways. Furthermore, we discussed the interaction between HIF-1α and other biological pathways such as oxidative stress; however, a spotlight has been focused on certain potential signalling contributed to the HIF-1α pathway. HIF-1α is an essential regulator of oxygen balance within cells which affects and controls the expression of thousands of genes related to sustaining homeostasis as oxygen levels fluctuate. HIF-1α's role in ischemic stroke strongly depends on the duration and severity of brain damage after onset. HIF-1α remains difficult to investigate, particularly in ischemic stroke, due to alterations in the acute and chronic phases of the disease, as well as discrepancies between the penumbra and ischemic core. This review emphasizes these contrasts and analyzes the future of this intriguing and demanding field.
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Affiliation(s)
- Nashwa Amin
- Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China; Department of Zoology, Faculty of Science, Aswan University, Egypt; Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Irum Naz Abbasi
- Institute of Systemic Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Fei Wu
- Institute of Systemic Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Zongjie Shi
- Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China
| | - Javaria Sundus
- Institute of Systemic Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Azhar Badry
- Institute of Systemic Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Xia Yuan
- Institute of Systemic Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Bing-Xin Zhao
- Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China
| | - Jie Pan
- Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China
| | - Xiao-Dan Mi
- Center for Rehabilitation Medicine, Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Department of Rehabilitation Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Yuhuan Luo
- Department of Pediatrics, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yu Geng
- Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China
| | - Marong Fang
- Institute of Systemic Medicine, Zhejiang University School of Medicine, Hangzhou, China; Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
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Lu Y, Elrod J, Herrmann M, Knopf J, Boettcher M. Neutrophil Extracellular Traps: A Crucial Factor in Post-Surgical Abdominal Adhesion Formation. Cells 2024; 13:991. [PMID: 38891123 PMCID: PMC11171752 DOI: 10.3390/cells13110991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 05/27/2024] [Accepted: 06/05/2024] [Indexed: 06/21/2024] Open
Abstract
Post-surgical abdominal adhesions, although poorly understood, are highly prevalent. The molecular processes underlying their formation remain elusive. This review aims to assess the relationship between neutrophil extracellular traps (NETs) and the generation of postoperative peritoneal adhesions and to discuss methods for mitigating peritoneal adhesions. A keyword or medical subject heading (MeSH) search for all original articles and reviews was performed in PubMed and Google Scholar. It included studies assessing peritoneal adhesion reformation after abdominal surgery from 2003 to 2023. After assessing for eligibility, the selected articles were evaluated using the Critical Appraisal Skills Programme checklist for qualitative research. The search yielded 127 full-text articles for assessment of eligibility, of which 7 studies met our criteria and were subjected to a detailed quality review using the Critical Appraisal Skills Programme (CASP) checklist. The selected studies offer a comprehensive analysis of adhesion pathogenesis with a special focus on the role of neutrophil extracellular traps (NETs) in the development of peritoneal adhesions. Current interventional strategies are examined, including the use of mechanical barriers, advances in regenerative medicine, and targeted molecular therapies. In particular, this review emphasizes the potential of NET-targeted interventions as promising strategies to mitigate postoperative adhesion development. Evidence suggests that in addition to their role in innate defense against infections and autoimmune diseases, NETs also play a crucial role in the formation of peritoneal adhesions after surgery. Therefore, therapeutic strategies that target NETs are emerging as significant considerations for researchers. Continued research is vital to fully elucidate the relationship between NETs and post-surgical adhesion formation to develop effective treatments.
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Affiliation(s)
- Yuqing Lu
- Department of Pediatric Surgery, University Medical Center Mannheim, University of Heidelberg, 68167 Mannheim, Germany
| | - Julia Elrod
- Department of Pediatric Surgery, University Medical Center Mannheim, University of Heidelberg, 68167 Mannheim, Germany
| | - Martin Herrmann
- Department of Pediatric Surgery, University Medical Center Mannheim, University of Heidelberg, 68167 Mannheim, Germany
- Department of Internal Medicine 3—Rheumatology and Immunology, Friedrich Alexander University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich Alexander University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany
| | - Jasmin Knopf
- Department of Pediatric Surgery, University Medical Center Mannheim, University of Heidelberg, 68167 Mannheim, Germany
| | - Michael Boettcher
- Department of Pediatric Surgery, University Medical Center Mannheim, University of Heidelberg, 68167 Mannheim, Germany
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S Temperley T, Temperley HC, O'Sullivan NJ, Corr A, Brennan I, Kelly ME, Prior L. Tracheoesophageal fistula development following radiotherapy and tyrosine kinase inhibitors in a patient with advanced follicular thyroid carcinoma: a case-based review. Ir J Med Sci 2024; 193:1143-1147. [PMID: 37922099 DOI: 10.1007/s11845-023-03559-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 10/23/2023] [Indexed: 11/05/2023]
Abstract
INTRODUCTION Tracheoesophageal fistulas (TEF) are a rare complication that can occur in patients with radioactive iodine refractory metastatic follicular thyroid carcinoma (FTC) following treatment with radiotherapy (RT) and tyrosine kinase inhibitors (TKI). METHODS We describe the case of a TEF development in a 69-year-old male who underwent targeted therapy TKIs and adjuvant RT for radioactive iodine refractory FTC. RESULTS In the case, staging investigations revealed a metastatic, poorly differentiated FTC refractory to radioactive iodine. After 2 years of disease control on Lenvatinib, the patient's condition progressed, necessitating a switch to Cabozantinib. Soon after, they presented with haemoptysis secondary to invasion of the primary thyroid tumour into the trachea. Radical radiotherapy (45 Gy/30 fractions) was also administered to the thyroid gland, ultimately complicated by radiation necrosis. Four months post-completion of RT and recommencing TKI, the patient presented with haemoptysis and hoarseness secondary to recurrent laryngeal nerve compression and tracheal invasion, as well as dysphagia secondary to oesophageal compression. Following an acute presentation with intractable throat pain, investigations revealed a TEF. Surgical and endoscopic management was deemed inappropriate given the patient's rapid deterioration and anatomical position of the TEF, and therefore a palliative approach was taken. CONCLUSION This case report highlights a rare cause of TEF development in a patient having TKI therapy post-RT for advanced FTC. It highlights the importance of monitoring TEF development in this cohort of patients. It demonstrates the importance of patient counselling and education regarding treatment options and the rare side effects of treatments.
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Affiliation(s)
- Tatiana S Temperley
- School of Medicine, University of Limerick, Limerick, Ireland
- Department of Oncology, The Beacon Hospital, Dublin, Ireland
| | - Hugo C Temperley
- Department of Radiology, St. James's Hospital, Dublin, Ireland.
- Department of Surgery, St. James's Hospital, Dublin, Ireland.
| | | | - Alison Corr
- Department of Radiology, St. James's Hospital, Dublin, Ireland
| | - Ian Brennan
- Department of Radiology, St. James's Hospital, Dublin, Ireland
| | - Michael E Kelly
- Department of Surgery, St. James's Hospital, Dublin, Ireland
| | - Lisa Prior
- Department of Oncology, The Beacon Hospital, Dublin, Ireland
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Shukla AK, Yoon S, Oh SO, Lee D, Ahn M, Kim BS. Advancement in Cancer Vasculogenesis Modeling through 3D Bioprinting Technology. Biomimetics (Basel) 2024; 9:306. [PMID: 38786516 PMCID: PMC11118135 DOI: 10.3390/biomimetics9050306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 05/15/2024] [Accepted: 05/15/2024] [Indexed: 05/25/2024] Open
Abstract
Cancer vasculogenesis is a pivotal focus of cancer research and treatment given its critical role in tumor development, metastasis, and the formation of vasculogenic microenvironments. Traditional approaches to investigating cancer vasculogenesis face significant challenges in accurately modeling intricate microenvironments. Recent advancements in three-dimensional (3D) bioprinting technology present promising solutions to these challenges. This review provides an overview of cancer vasculogenesis and underscores the importance of precise modeling. It juxtaposes traditional techniques with 3D bioprinting technologies, elucidating the advantages of the latter in developing cancer vasculogenesis models. Furthermore, it explores applications in pathological investigations, preclinical medication screening for personalized treatment and cancer diagnostics, and envisages future prospects for 3D bioprinted cancer vasculogenesis models. Despite notable advancements, current 3D bioprinting techniques for cancer vasculogenesis modeling have several limitations. Nonetheless, by overcoming these challenges and with technological advances, 3D bioprinting exhibits immense potential for revolutionizing the understanding of cancer vasculogenesis and augmenting treatment modalities.
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Affiliation(s)
- Arvind Kumar Shukla
- School of Biomedical Convergence Engineering, Pusan National University, Yangsan 50612, Republic of Korea
| | - Sik Yoon
- Department of Anatomy and Convergence Medical Sciences, Pusan National University College of Medicine, Yangsan 50612, Republic of Korea
- Immune Reconstitution Research Center of Medical Research Institute, Pusan National University College of Medicine, Yangsan 50612, Republic of Korea
| | - Sae-Ock Oh
- Research Center for Molecular Control of Cancer Cell Diversity, Pusan National University, Yangsan 50612, Republic of Korea
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
| | - Dongjun Lee
- Department of Convergence Medicine, Pusan National University College of Medicine, Yangsan 50612, Republic of Korea
| | - Minjun Ahn
- Medical Research Institute, Pusan National University, Yangsan 50612, Republic of Korea
| | - Byoung Soo Kim
- School of Biomedical Convergence Engineering, Pusan National University, Yangsan 50612, Republic of Korea
- Medical Research Institute, Pusan National University, Yangsan 50612, Republic of Korea
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Lin X, Kang K, Chen P, Zeng Z, Li G, Xiong W, Yi M, Xiang B. Regulatory mechanisms of PD-1/PD-L1 in cancers. Mol Cancer 2024; 23:108. [PMID: 38762484 PMCID: PMC11102195 DOI: 10.1186/s12943-024-02023-w] [Citation(s) in RCA: 130] [Impact Index Per Article: 130.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 05/10/2024] [Indexed: 05/20/2024] Open
Abstract
Immune evasion contributes to cancer growth and progression. Cancer cells have the ability to activate different immune checkpoint pathways that harbor immunosuppressive functions. The programmed death protein 1 (PD-1) and programmed cell death ligands (PD-Ls) are considered to be the major immune checkpoint molecules. The interaction of PD-1 and PD-L1 negatively regulates adaptive immune response mainly by inhibiting the activity of effector T cells while enhancing the function of immunosuppressive regulatory T cells (Tregs), largely contributing to the maintenance of immune homeostasis that prevents dysregulated immunity and harmful immune responses. However, cancer cells exploit the PD-1/PD-L1 axis to cause immune escape in cancer development and progression. Blockade of PD-1/PD-L1 by neutralizing antibodies restores T cells activity and enhances anti-tumor immunity, achieving remarkable success in cancer therapy. Therefore, the regulatory mechanisms of PD-1/PD-L1 in cancers have attracted an increasing attention. This article aims to provide a comprehensive review of the roles of the PD-1/PD-L1 signaling in human autoimmune diseases and cancers. We summarize all aspects of regulatory mechanisms underlying the expression and activity of PD-1 and PD-L1 in cancers, including genetic, epigenetic, post-transcriptional and post-translational regulatory mechanisms. In addition, we further summarize the progress in clinical research on the antitumor effects of targeting PD-1/PD-L1 antibodies alone and in combination with other therapeutic approaches, providing new strategies for finding new tumor markers and developing combined therapeutic approaches.
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Affiliation(s)
- Xin Lin
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
- FuRong Laboratory, Changsha, 410078, Hunan, China
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, 410008, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, Hunan, China
| | - Kuan Kang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
- FuRong Laboratory, Changsha, 410078, Hunan, China
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, 410008, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, Hunan, China
| | - Pan Chen
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Zhaoyang Zeng
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
- FuRong Laboratory, Changsha, 410078, Hunan, China
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, 410008, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, Hunan, China
| | - Guiyuan Li
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
- FuRong Laboratory, Changsha, 410078, Hunan, China
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, 410008, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, Hunan, China
| | - Wei Xiong
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
- FuRong Laboratory, Changsha, 410078, Hunan, China
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, 410008, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, Hunan, China
| | - Mei Yi
- Department of Dermotology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
| | - Bo Xiang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China.
- FuRong Laboratory, Changsha, 410078, Hunan, China.
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, 410008, Hunan, China.
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, Hunan, China.
- Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Tongzipo Road, Changsha, 410013, Hunan, China.
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Macartney RA, Weaver E, Irwin R, Wylie MP, Burke GA, Lamprou DA. Co-delivery of VEGF and amoxicillin using LP-coated co-axial electrospun fibres for the potential treatment of diabetic wounds. BIOMATERIALS ADVANCES 2024; 158:213765. [PMID: 38242058 DOI: 10.1016/j.bioadv.2024.213765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 01/05/2024] [Accepted: 01/07/2024] [Indexed: 01/21/2024]
Abstract
Diabetic complications present throughout a wide range of body tissues, however one of the most widely recognised complications remains to be chronic diabetic wounds. Current treatment options largely rely on standard wound treatment routines which provide no promotion of wound healing mechanisms at different physiological stages of repair. Recently materials produced using novel additive manufacturing techniques have been receiving attention for applications in wound care and tissue repair. Additive manufacturing techniques have recently been used in the interest of targeted drug delivery and production of novel materials resembling characteristics of native tissues. The potential to exploit these highly tailorable manufacturing techniques for the design of novel wound care remedies is highly desirable. In the present study two additive manufacturing techniques are combined to produce a scaffold for the treatment of diabetic wounds. The combination of microfluidic manufacturing of an antimicrobial liposome (LP) formulation and a coaxial electrospinning method incorporating both antimicrobial and proangiogenic factors allowed dual delivery of therapeutics to target both infection and lack of vascularisation at wound sites. The coaxial fibres comprised of a polyvinyl alcohol (PVA) core containing vascular endothelial growth factor (VEGF) and a poly (l-lactide-co-ε-caprolactone) (PLCL) shell blended with amoxicillin (Amox). Additionally, a liposomal formulation was produced to incorporate Amox and adhered to the surface of fibres loaded with Amox and VEGF. The liposomal loading provided the potential to deliver a much higher, more clinically relevant dose of Amox without detrimentally changing the mechanical properties of the material. The growth factor release was sustained up to 7-days in vitro. The therapeutic effect of the antibiotic loading was analysed using a disk diffusion method with a significant increase in zone diameter following LP adhesion, proving the full scaffold system had improved efficacy against both Gram-positive and Gram-negative strains. Additionally, the dual-loaded scaffolds show enhanced potential for supporting vascular growth in vitro, as demonstrated via a viability assay and tubule formation studies. Results showed a significant increase in the average total number of tubes from 10 in control samples to 77 in samples fully-loaded with Amox and VEGF.
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Affiliation(s)
- Robyn A Macartney
- Nanotechnology & Integrated Bioengineering Centre (NIBEC), School of Engineering, Ulster University, York Street, Belfast BT15 1ED, UK; School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.
| | - Edward Weaver
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Robyn Irwin
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Matthew P Wylie
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - George A Burke
- Nanotechnology & Integrated Bioengineering Centre (NIBEC), School of Engineering, Ulster University, York Street, Belfast BT15 1ED, UK
| | - Dimitrios A Lamprou
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.
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Ezelarab HAA, Abd El-Hafeez AA, Ali TFS, Sayed AM, Hassan HA, Beshr EAM, Abbas SH. New 2-oxoindole derivatives as multiple PDGFRα/ß and VEGFR-2 tyrosine kinase inhibitors. Bioorg Chem 2024; 145:107234. [PMID: 38412650 DOI: 10.1016/j.bioorg.2024.107234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 02/18/2024] [Accepted: 02/19/2024] [Indexed: 02/29/2024]
Abstract
Two new series of N-aryl acetamides 6a-o and benzyloxy benzylidenes 9a-p based 2-oxoindole derivatives were designed as potent antiproliferative multiple kinase inhibitors. The results of one-dose NCI antiproliferative screening for compounds 6a-o and 9a-p elucidated that the most promising antiproliferative scaffolds were 6f and 9f, which underwent five-dose testing. Notably, the amido congener 6f was the most potent derivative towards pancreatic ductal adenocarcinoma MDA-PATC53 and PL45 cell lines (IC50 = 1.73 µM and 2.40 µM, respectively), and the benzyloxy derivative 9f was the next potent one with IC50 values of 2.85 µM and 2.96 µM, respectively. Both compounds 6f and 9f demonstrated a favorable safety profile when tested against normal prostate epithelial cells (RWPE-1). Additionally, compound 6f displayed exceptional selectivity as a multiple kinase inhibitor, particularly targeting PDGFRα, PDGFRβ, and VEGFR-2 kinases, with IC50 values of 7.41 nM, 6.18 nM, and 7.49 nM, respectively. In contrast, the reference compound Sunitinib exhibited IC50 values of 43.88 nM, 2.13 nM, and 78.46 nM against the same kinases. The derivative 9f followed closely, with IC50 values of 9.9 nM, 6.62 nM, and 22.21 nM for the respective kinases. Both 6f and 9f disrupt the G2/M cell cycle transition by upregulating p21 and reducing CDK1 and cyclin B1 mRNA levels. The interplay between targeted kinases and these cell cycle regulators underpins the G2/M cell cycle arrest induced by our compounds. Also, compounds 6f and 9f fundamentally resulted in entering MDA-PATC53 cells into the early stage of apoptosis with good percentages compared to the positive control Sunitinib. The in silico molecular-docking outcomes of scaffolds 6a-o and 9a-p in VEGFR-2, PDGFRα, and PDGFRβ active sites depicted their ability to adopt essential binding interactions like the reference Sunitinib. Our designed analogs, specifically 6f and 9f, possess promising antiproliferative and kinase inhibitory properties, making them potential candidates for further therapeutic development.
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Affiliation(s)
- Hend A A Ezelarab
- Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt
| | - Amer Ali Abd El-Hafeez
- Pharmacology and Experimental Oncology Unit, Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo, Egypt.
| | - Taha F S Ali
- Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt
| | - Ahmed M Sayed
- Department of Pharmacognosy, Faculty of Pharmacy, Nahda University, 62513 Beni-Suef, Egypt; Department of Pharmacognosy, Collage of Pharmacy, Almaaqal University, 61014 Basrah, Iraq
| | - Heba A Hassan
- Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt.
| | - Eman A M Beshr
- Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt
| | - Samar H Abbas
- Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt.
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Khater I, Nassar A. Targeting EGFR and VEGFR-2 Kinases With Nanoparticles: A Computational Approach for Cancer Therapy Advancement. Cancer Invest 2024; 42:176-185. [PMID: 38486424 DOI: 10.1080/07357907.2024.2328529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 03/05/2024] [Indexed: 03/23/2024]
Abstract
The study investigates titanium and zinc nanoparticles as inhibitors for the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor-2 (VEGFR-2), pivotal regulators of cell processes. VEGFR-2 activation fuels tumor angiogenesis in cancer cells, sustaining malignant tissue expansion. Molecular docking analysis illustrates the nanoparticles' binding to the active sites, inhibiting the phosphorylation of key proteins in downstream signaling. This inhibition offers a promising therapeutic approach to impede cancer-related signaling, potentially slowing down aberrant protein cascades controlled by EGFR and VEGFR-2. The findings propose a novel avenue for cancer treatment, targeting abnormal growth pathways using titanium and zinc nanoparticles.
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Affiliation(s)
- Ibrahim Khater
- Biophysics Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Aaya Nassar
- Biophysics Department, Faculty of Science, Cairo University, Giza, Egypt
- Department of Clinical Research and Leadership, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA
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Dzator JSA, Smith RA, Coupland KG, Howe PRC, Griffiths LR. Associations between Cerebrovascular Function and the Expression of Genes Related to Endothelial Function in Hormonal Migraine. Int J Mol Sci 2024; 25:1694. [PMID: 38338971 PMCID: PMC10855027 DOI: 10.3390/ijms25031694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 01/23/2024] [Accepted: 01/26/2024] [Indexed: 02/12/2024] Open
Abstract
There is evidence to suggest that hormonal migraine is associated with altered cerebrovascular function. We aimed to investigate whether the expression of genes related to endothelial function in venous blood (1) might influence cerebrovascular function, (2) differs between hormonal migraineur and non-migraineur women, and (3) changes following resveratrol supplementation. This study utilised data obtained from 87 women (59 hormonal migraineurs and 28 controls) where RNA from venous blood was used to quantify gene expression and transcranial Doppler ultrasound was used to evaluate cerebrovascular function. Spearman's correlation analyses were performed between gene expression, cerebrovascular function, and migraine-related disability. We compared the expression of genes associated with endothelial function between migraineurs and non-migraineurs, and between resveratrol and placebo. The expression of several genes related to endothelial function was associated with alterations in cerebrovascular function. Notably, the expression of CALCA was associated with increased neurovascular coupling capacity (p = 0.013), and both CALCA (p = 0.035) and VEGF (p = 0.014) expression were associated with increased cerebral blood flow velocity in the overall study population. Additionally, VCAM1 expression correlated with decreased pulsatility index (a measure of cerebral arterial stiffness) (p = 0.009) and headache impact test-6 scores (p = 0.007) in the migraineurs. No significant differences in gene expression were observed between migraineurs and controls, or between placebo and resveratrol treatments in migraineurs. Thus, altering the expression of genes related to endothelial function may improve cerebrovascular function and decrease migraine-related disability.
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Affiliation(s)
- Jemima S. A. Dzator
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW 2308, Australia (P.R.C.H.)
- School of Pharmacy and Medical Sciences, Griffith University, Gold Coast, QLD 4222, Australia
| | - Robert A. Smith
- Genomics Research Centre, Centre for Genomics and Personalised Health, Queensland University of Technology, Brisbane, QLD 4059, Australia
| | - Kirsten G. Coupland
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW 2308, Australia (P.R.C.H.)
- Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
| | - Peter R. C. Howe
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW 2308, Australia (P.R.C.H.)
- Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia
- Centre for Health Research, University of Southern Queensland, Raceview, QLD 4350, Australia
| | - Lyn R. Griffiths
- Genomics Research Centre, Centre for Genomics and Personalised Health, Queensland University of Technology, Brisbane, QLD 4059, Australia
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Alsakhen N, Radwan ES, Zafer I, Abed Alfattah H, Shamkh IM, Rehman MT, Shahwan M, Khan KA, Ahmed SA. Computational analysis of bevacizumab binding with protein receptors for its potential anticancer activity. J Biomol Struct Dyn 2024:1-21. [PMID: 38281913 DOI: 10.1080/07391102.2024.2307445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 01/08/2024] [Indexed: 01/30/2024]
Abstract
Breast cancer poses a significant global challenge, prompting researchers to explore novel approaches for potential treatments. In this study, we investigated the binding free energy (ΔG) of bevacizumab, an anti-cancer therapy targeting angiogenesis through the inhibition of vascular endothelial growth factor (VEGF), with various proto-oncogenes including CDK4, EGFR, frizzled, IGFR, OmoMYC, and KIT. Our in-silico investigation revealed that hydrogen bonding is pivotal in inducing conformational changes within the DNA structure, impeding its replication and preventing cell death. Molecular docking results revealed the presence of crucial hydrogen bonds and supported the formation of stable bevacizumab complexes. The molecular docking scores for the tested complexes were CDK4 (Score = -7.2 kcal/mol), EGFR (Score = -8.5 kcal/mol), frizzled (Score = -6.9 kcal/mol), IGFR (Score = -7.8 kcal/mol), KIT (Score = -6.5 kcal/mol), and MYC (Score = -8.3 kcal/mol). The binding mode demonstrated vital hydrogen bonds correlated with the observed energy gap. Notably, the calculated binding free energies of the tested compounds are as follows: CDK4 (ΔG = 24275.195 ± 6411.293 kJ/mol), EGFR (ΔG = 363273.625 ± 8731.466 kJ/mol), frizzled (ΔG = 181751.990 ± 28438.515 kJ/mol), IGFR (ΔG = 162414.725 ± 10728.367 kJ/mol), KIT (ΔG = 40162.585 ± 4331.017 kJ/mol), and MYC (ΔG = 434783.463 ± 53989.676 kJ/mol). Furthermore, through extensive 100 ns MD simulations, we observed the formation of a stable bevacizumab complex structure. The simulations confirmed the stability of the bevacizumab complex with the proto-oncogenes. The results of this study highlight the potential of bevacizumab complex as a promising candidate for anticancer treatment. The identification of hydrogen bonding, along with the calculated binding free energies and molecular docking scores, provides valuable insights into the molecular interactions and stability of the bevacizumab complexes. These findings and the extensive MD simulations open new avenues for future research and development of bevacizumab as a targeted therapy for breast cancer and other related malignancies.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Nada Alsakhen
- Department of Chemistry, Faculty of Science, The Hashemite University, Zarqa, Jordan
| | | | - Imran Zafer
- Department of Bioinformatics and Computational Biology, Virtual University, Lahore, Pakistan
| | | | - Israa M Shamkh
- Botany and Microbiology department, Faculty of Science, Cairo University, Giza, Egypt
| | - Md Tabish Rehman
- College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
- Center for Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| | - Moayad Shahwan
- Center for Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
- Department of Clinical Sciences, College of Pharmacy and Health Sciences, Ajman University, Ajman, United Arab Emirates
| | - Khalid Ali Khan
- Applied College, Center of Bee Research and its Products, Unit of Bee Research and Honey Production, and Research Center for Advanced Materials Science (RCAMS), King Khalid University, Abha, Saudi Arabia
| | - Shimaa A Ahmed
- Department of Chemistry, Faculty of Science, Beni-Suef University, Beni Suef, Egypt
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Gayatri V, Krishna Prasad M, Mohandas S, Nagarajan S, Kumaran K, Ramkumar KM. Crosstalk between inflammasomes, inflammation, and Nrf2: Implications for gestational diabetes mellitus pathogenesis and therapeutics. Eur J Pharmacol 2024; 963:176241. [PMID: 38043778 DOI: 10.1016/j.ejphar.2023.176241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 11/21/2023] [Accepted: 11/28/2023] [Indexed: 12/05/2023]
Abstract
The role of inflammasomes in gestational diabetes mellitus (GDM) has emerged as a critical area of research in recent years. Inflammasomes, key components of the innate immune system, are now recognized for their involvement in the pathogenesis of GDM. Activation of inflammasomes in response to various triggers during pregnancy can produce pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and interleukin-18 (IL-18), contributing to systemic inflammation and insulin resistance. This dysregulation not only impacts maternal health but also poses significant risks to fetal development and long-term health outcomes. Understanding the intricate interplay between inflammasomes and GDM holds promise for developing novel therapeutic strategies and interventions to mitigate the adverse effects of this condition on both mothers and their offspring. Researchers have elucidated that targeting inflammasomes using anti-inflammatory drugs and compounds can effectively reduce inflammation in GDM. Furthermore, the addition of nuclear factor erythroid 2-related factor 2 (Nrf2) to this complex mechanism opens novel avenues for therapeutics. The antioxidant properties of Nrf2 may potentially suppress inflammasome activation in GDM. This comprehensive review investigates the intricate relationship between inflammasomes and GDM, emphasizing the pivotal role of inflammation in its pathogenesis. It also sheds light on potential therapeutic strategies targeting inflammasome activation and explores the role of Nrf2 in mitigating inflammation in GDM.
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Affiliation(s)
- Vijaya Gayatri
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603 203, Tamil Nadu, India
| | - Murali Krishna Prasad
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603 203, Tamil Nadu, India
| | - Sundhar Mohandas
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603 203, Tamil Nadu, India
| | - Sanjushree Nagarajan
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603 203, Tamil Nadu, India
| | - Kriya Kumaran
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603 203, Tamil Nadu, India
| | - Kunka Mohanram Ramkumar
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603 203, Tamil Nadu, India.
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Ya J, Pellumbaj J, Hashmat A, Bayraktutan U. The Role of Stem Cells as Therapeutics for Ischaemic Stroke. Cells 2024; 13:112. [PMID: 38247804 PMCID: PMC10814781 DOI: 10.3390/cells13020112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 01/01/2024] [Accepted: 01/04/2024] [Indexed: 01/23/2024] Open
Abstract
Stroke remains one of the leading causes of death and disability worldwide. Current reperfusion treatments for ischaemic stroke are limited due to their narrow therapeutic window in rescuing ischaemic penumbra. Stem cell therapy offers a promising alternative. As a regenerative medicine, stem cells offer a wider range of treatment strategies, including long-term intervention for chronic patients, through the reparation and replacement of injured cells via mechanisms of differentiation and proliferation. The purpose of this review is to evaluate the therapeutic role of stem cells for ischaemic stroke. This paper discusses the pathology during acute, subacute, and chronic phases of cerebral ischaemic injury, highlights the mechanisms involved in mesenchymal, endothelial, haematopoietic, and neural stem cell-mediated cerebrovascular regeneration, and evaluates the pre-clinical and clinical data concerning the safety and efficacy of stem cell-based treatments. The treatment of stroke patients with different types of stem cells appears to be safe and efficacious even at relatively higher concentrations irrespective of the route and timing of administration. The priming or pre-conditioning of cells prior to administration appears to help augment their therapeutic impact. However, larger patient cohorts and later-phase trials are required to consolidate these findings.
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Affiliation(s)
| | | | | | - Ulvi Bayraktutan
- Academic Unit of Mental Health and Clinical Neurosciences, Queens Medical Centre, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK
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Ateeq M, Broadwin M, Sellke FW, Abid MR. Extracellular Vesicles' Role in Angiogenesis and Altering Angiogenic Signaling. Med Sci (Basel) 2024; 12:4. [PMID: 38249080 PMCID: PMC10801520 DOI: 10.3390/medsci12010004] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 12/15/2023] [Accepted: 12/21/2023] [Indexed: 01/23/2024] Open
Abstract
Angiogenesis, the process of new blood vessels formation from existing vasculature, plays a vital role in development, wound healing, and various pathophysiological conditions. In recent years, extracellular vesicles (EVs) have emerged as crucial mediators in intercellular communication and have gained significant attention for their role in modulating angiogenic processes. This review explores the multifaceted role of EVs in angiogenesis and their capacity to modulate angiogenic signaling pathways. Through comprehensive analysis of a vast body of literature, this review highlights the potential of utilizing EVs as therapeutic tools to modulate angiogenesis for both physiological and pathological purposes. A good understanding of these concepts holds promise for the development of novel therapeutic interventions targeting angiogenesis-related disorders.
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Affiliation(s)
- Maryam Ateeq
- Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, RI 02903, USA; (M.A.); (M.B.); (F.W.S.)
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Mark Broadwin
- Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, RI 02903, USA; (M.A.); (M.B.); (F.W.S.)
| | - Frank W. Sellke
- Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, RI 02903, USA; (M.A.); (M.B.); (F.W.S.)
| | - M. Ruhul Abid
- Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, RI 02903, USA; (M.A.); (M.B.); (F.W.S.)
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50
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Afaq F, Agarwal S, Bajpai P, Diffalha SA, Kim HG, Peter S, Khushman M, Chauhan SC, Mukherjee P, Varambally S, Manne U. Targeting of oncogenic AAA-ATPase TRIP13 reduces progression of pancreatic ductal adenocarcinoma. Neoplasia 2024; 47:100951. [PMID: 38039923 PMCID: PMC10716004 DOI: 10.1016/j.neo.2023.100951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 11/21/2023] [Accepted: 11/21/2023] [Indexed: 12/03/2023]
Abstract
Thyroid hormone receptor-interacting protein 13 (TRIP13) is involved in cancer progression, but its role in pancreatic ductal adenocarcinoma (PDAC) is unknown. Thus, we assessed the expression, functional role, and mechanism of action of TRIP13 in PDAC. We further examined the efficacy of TRIP13 inhibitor, DCZ0415, alone or in combination with gemcitabine on malignant phenotypes, tumor progression, and immune response. We found that TRIP13 was overexpressed in human PDACs relative to corresponding normal pancreatic tissues. TRIP13 knockdown or treatment of PDAC cells with DCZ0415 reduced proliferation and colony formation, and induced G2/M cell cycle arrest and apoptosis. Additionally, TRIP13 knockdown or targeting with DCZ0415 reduced the migration and invasion of PDAC cells by increasing E-cadherin and decreasing N-cadherin and vimentin. Pharmacologic targeting or silencing of TRIP13 also resulted in reduce expression of FGFR4 and STAT3 phosphorylation, and downregulation of the Wnt/β-catenin pathway. In immunocompromised mouse models of PDAC, knockdown of TRIP13 or treatment with DCZ0415 reduced tumor growth and metastasis. In an immunocompetent syngeneic PDAC model, DCZ0415 treatment enhanced the immune response by lowering expression of PD1/PDL1, increasing granzyme B/perforin expression, and facilitating infiltration of CD3/CD4 T-cells. Further, DCZ0415 potentiated the anti-metastatic and anti-tumorigenic activities of gemcitabine by reducing proliferation and angiogenesis and by inducing apoptosis and the immune response. These preclinical findings show that TRIP13 is involved in PDAC progression and targeting of TRIP13 augments the anticancer effect of gemcitabine.
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Affiliation(s)
- Farrukh Afaq
- Department of Pathology, University of Alabama at Birmingham, USA
| | - Sumit Agarwal
- Department of Pathology, University of Alabama at Birmingham, USA
| | - Prachi Bajpai
- Department of Pathology, University of Alabama at Birmingham, USA
| | - Sameer Al Diffalha
- Department of Pathology, University of Alabama at Birmingham, USA; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, USA
| | - Hyung-Gyoon Kim
- Department of Pathology, University of Alabama at Birmingham, USA
| | - Shajan Peter
- Department of Medicine, Division of Gastroenterology, University of Alabama at Birmingham, USA
| | - Moh'd Khushman
- Department of Medicine, Division of Medical Oncology, Washington University in St. Louis, USA
| | - Subhash C Chauhan
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, USA
| | - Priyabrata Mukherjee
- Department of Pathology, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Sooryanarayana Varambally
- Department of Pathology, University of Alabama at Birmingham, USA; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, USA
| | - Upender Manne
- Department of Pathology, University of Alabama at Birmingham, USA; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, USA.
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