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Wu Y, Wang B, Mao X, Chen W, Akber Aisa H. Harmine derivative B-9-3 inhibits non-small cell lung cancer via the VEGFA/PI3K/AKT pathway. Front Pharmacol 2025; 16:1526952. [PMID: 40432889 PMCID: PMC12107193 DOI: 10.3389/fphar.2025.1526952] [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: 11/12/2024] [Accepted: 04/18/2025] [Indexed: 05/29/2025] Open
Abstract
Background This study aimed to investigate the molecular mechanism by which the Harmine derivative B-9-3 inhibits angiogenesis and promotes apoptosis in non-small cell lung cancer (NSCLC). Methods Three non-small cell lung cancer (NSCLC) models (human NSCLC cell line A549, human lung squamous cell carcinoma cell line H226, human large cell lung carcinoma cell line H460) were established. Cell proliferation was assessed using CCK-8 assays and colony formation assays. Cell motility was evaluated through scratch wound healing, invasion, and migration assays. Cell apoptosis was analyzed by Hoechst 33258 staining, AO/EB fluorescence staining, and flow cytometry. Real-time PCR was used to measure the mRNA expression of B-cell lymphoma/leukemia-2 (Bcl-2), Bcl-2-associated X protein (Bax), and Caspase-3, while Western blotting was performed to assess the protein levels of vascular endothelial growth factor A (VEGFA), phosphatidylinositol 3-kinases p110 Beta (PI3K), phospho-phosphatidylinositol 3-kinases (p-PI3K), protein kinase B (AKT), phosphorylated protein kinase B (p-AKT), Bax, Bcl-2, and Caspase-3. Results Compared to the control group, B-9-3 (50, 100, 200 μg/mL) inhibited the growth and motility of the three types of lung cancer cells, suppressed cell invasion and migration, and promoted cell apoptosis and necrosis. The apoptosis rates in three types of non-small cell lung cancer (NSCLC) cells were significantly increased. The mRNA expressions of Bax and Caspase-3 were markedly upregulated, while that of Bcl-2 was significantly downregulated. Additionally, the protein levels of VEGFA, p-PI3K/PI3K, p-AKT/AKT, and Bcl-2 were notably reduced, whereas the protein levels of Bax and Caspase-3 were significantly elevated. Conclusion The harmine derivative B-9-3 may exert its anti-NSCLC effects by inhibiting angiogenesis and promoting lung cancer cell apoptosis via the VEGFA/PI3K/AKT signaling pathway.
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Affiliation(s)
- Yuche Wu
- Xinjiang Technical Institute of Physics and Chemistry Chinese Academy of Sciences, Urumqi, Xinjiang, China
| | - Bing Wang
- The Fourth Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Xuwen Mao
- College of Pharmacy, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Wei Chen
- Xinjiang Huashidan Pharmaceutical Co., Ltd., Urumqi, Xinjiang, China
| | - Haji Akber Aisa
- Xinjiang Technical Institute of Physics and Chemistry Chinese Academy of Sciences, Urumqi, Xinjiang, China
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2
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Duzgun Z, Korkmaz FD, Akgün E. FDI-6 inhibits VEGF-B expression in metastatic breast cancer: a combined in vitro and in silico study. Mol Divers 2025; 29:1069-1078. [PMID: 38853176 PMCID: PMC11909019 DOI: 10.1007/s11030-024-10891-z] [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: 03/20/2024] [Accepted: 05/09/2024] [Indexed: 06/11/2024]
Abstract
Angiogenesis is the process by which new blood vessels are formed to meet the oxygen and nutrient needs of tissues. This process is vitally important in many physiological and pathological conditions such as tumor growth, metastasis, and chronic inflammation. Although the relationship of FDI-6 compound with FOXM1 protein is well known in the literature, its relationship with angiogenesis is not adequately elucidated. This study investigates the relationship of FDI-6 with angiogenesis and vascular endothelial growth factor B (VEGF-B) protein expression alterations. Furthermore, the study aims to elucidate the in silico interaction of FDI-6 with the VEGFR1 protein, a key player in initiating the angiogenic process, which is activated through its binding with VEGF-B. Our results demonstrate a significant effect of FDI-6 on cell viability. Specifically, we determined that the IC50 value of FDI-6 in HUVEC cells after 24 h of treatment is 24.2 μM, and in MDA-MB-231 cells after 24 h of application, it is 10.8 μM. These findings suggest that the cytotoxic effect of FDI-6 varies depending on the cell type. In wound healing experiments, FDI-6 significantly suppressed wound closure in MDA-MB-231 cells but did not show a similar effect in HUVEC cells. This finding suggests FDI-6 may have potential cell-type-specific effects. Molecular docking studies reveal that FDI-6 exhibits a stronger interaction with the VEGFR1 protein compared to its inhibitor, a novel interaction not previously reported in the literature. Molecular dynamic simulation results demonstrate a stable interaction between FDI-6 and VEGFR1. This interaction suggests that FDI-6 might modulate mechanisms associated with angiogenesis. Our Western blot analysis results show regulatory effects of FDI-6 on the expression of the VEGF-B protein. We encourage exploration of FDI-6 as a potential therapeutic agent in pathological processes related to angiogenesis. In conclusion, this study provides a detailed examination of the relationship between FDI-6 and both the molecular interactions and protein expressions of VEGF-B. Our findings support FDI-6 as a potential therapeutic agent in pathological processes associated with angiogenesis.
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Affiliation(s)
- Zekeriya Duzgun
- Department of Medical Biology, Faculty of Medicine, Giresun University, Giresun, Turkey.
| | | | - Egemen Akgün
- Department of Medical Biology, Faculty of Medicine, Giresun University, Giresun, Turkey
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Gabr BS, Shalabi AR, Said MF, George RF. 3,5-Disubstituted pyrazoline as a promising core for anticancer agents: mechanisms of action and therapeutic potentials. Future Med Chem 2025; 17:725-745. [PMID: 40079157 PMCID: PMC11938987 DOI: 10.1080/17568919.2025.2476393] [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: 12/31/2024] [Accepted: 02/18/2025] [Indexed: 03/14/2025] Open
Abstract
The rapidly growing interest in the literature about the anticancer activity of 3,5-disubstituted pyrazolines and their promising therapeutic potentials/pharmacological properties, supported by the number of pyrazoline derivatives currently in clinical use or clinical trials, encouraged us to review the in vitro antiproliferative effects and biochemical investigations of probable mechanisms of action. Nevertheless, many reported pyrazoline-bearing compounds have anticancer activity without an explored mode of action, which opens new research avenues to examine their biochemical profiles further. Therefore, 3,5-disubstituted pyrazoline is a promising core that can be used to design new derivatives with anticancer activity based on the structure-activity relationship summarized in this review to obtain higher potency and selectivity.
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Affiliation(s)
- Basma S. Gabr
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Sinai University, EL-Arish, Egypt
| | - Abdelrahman R. Shalabi
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Sinai University, EL-Arish, Egypt
| | - Mona F. Said
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Riham F. George
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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Feng Z, Han C, Zhang N, Wang Y, Luo G, Gao X. An integrated strategy for deciphering the action mechanism of emplastrum: Prescription analysis- component identification- virtual screening and affinity testing in the case of Yaoshen Gao. JOURNAL OF ETHNOPHARMACOLOGY 2025; 342:119369. [PMID: 39842747 DOI: 10.1016/j.jep.2025.119369] [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: 11/26/2024] [Revised: 01/12/2025] [Accepted: 01/13/2025] [Indexed: 01/24/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Emplastrum has a long history of use in the clinical practice of traditional Chinese medicine (TCM), valued for its convenient external application and pronounced therapeutic effects. Traditionally, the emplastrum was composed of numerous herbal medicines. The elucidation of their mechanisms of action are of great importance. YaoShen Gao (YSG), as a traditional example of emplastrum, was composed of more than 20 medicinal herbs. Clinically, YSG has been used to treat benign prostatic hyperplasia (BPH). However, the active components and therapeutic targets of YSG remain unclear, requiring further investigation. AIM OF THE STUDY To establish an integrated strategy to uncover the mechanisms underlying the potential active ingredients and therapeutic targets in complex TCM emplastra, using YSG for BPH treatment as a case study. MATERIALS AND METHODS A BPH rat model was established via castration and testosterone propionate injections. The therapeutic efficacy of YSG was evaluated comprehensively through phenotypic, pathological, physiological, and biochemical analyses. Prescription analysis was conducted based on the principles of "monarch, minister, assistant, and courier," as well as clinical dosage and efficacy. Based on the strategy of representative compounds-single herbal medicine -YSG formulation, the chemical profile of YSG was performed using UPLC-Q Exactive Orbitrap- MS. Network pharmacology identified preliminary targets, while molecular docking and literature mining further narrowed these down. Finally, molecular dynamics simulations and Bio-Layer Interferometry (BLI) were used to validate binding affinities of active components to targets. RESULTS The efficacy indicators demonstrated that treatment of YSG significantly reduced prostate wet weight and prostate index in BPH rats, with notable improvements observed in glandular structure. Additionally, YSG inhibited the expression of inflammatory factors (TNF- α, IL- 8) and fibrosis-related proteins (VEGF, TGF-β). Twelve key herbal medicines were identified by prescription analysis from the 20 herbs in YSG, such as Cistanche deserticola, Epimedium sagittatum and so on. High-resolution mass spectrometry (HR-MS) characterized 125 chemical components, and Venn analysis identified 409 common targets between YSG components and BPH. Subsequently, GO and KEGG analyses revealed that these targets are predominantly involved in protein phosphorylation, cellular components, and key signaling pathways. Protein-protein interaction (PPI) analysis identified 10 key targets, suggesting that the therapeutic effects of YSG on BPH are mediated through 39 active compounds and 12 relevant signaling pathways. Molecular docking analysis identified 14 target-compound pairs, and literature supported their relevance in PI3K/AKT, VEGF, TNF, and TGF-β pathways. Molecular dynamics simulations and BLI further validated the strong interactions between representative target-small molecule pairs like AKT1 with bavachalcone (KD = 46.8 μM) and PIK3R1 with apigenin (KD = 47.9 μM). CONCLUSIONS A systematic strategy for identifying active ingredients and therapeutic targets in complex TCM emplastra was developed. YSG contains active components, including bavachalcone, apigenin, schisandrin C, liquiritigenin, 8-prenyldaidzein, estrone, isopimpinellin, 8-prenylkaempferol, which act on six key targets, such as AKT1 and PIK3R1, to regulate the AKT/PI3K, AGE-RAGE, AR, VEGF, TGF-β, TNF and others signaling pathways. These pathways further modulate cellular proliferation, fibrosis, inflammation, and angiogenesis, thereby effectively contributing to the treatment of BPH.
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Affiliation(s)
- ZhiYang Feng
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Chen Han
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Na Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Ying Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Gan Luo
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - XiaoYan Gao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
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Bawazir WA, Ali TE, Alsolimani AK, Assiri MA, Shati AA, Alfaifi MY, Elbehairi SEI. Novel ethyl 2-hydrazineylidenethiazolidin-5-ylidene acetate clubbed with coumarinylthiazolyl pyrazole system as potential VEGFR-2 inhibitors and apoptosis inducer: synthesis, cytotoxic evaluation, cell cycle, autophagy, in silico ADMET and molecular docking studies. RSC Adv 2025; 15:4829-4846. [PMID: 39957832 PMCID: PMC11822769 DOI: 10.1039/d5ra00250h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Accepted: 02/09/2025] [Indexed: 02/18/2025] Open
Abstract
Novel derivatives of ethyl 3-substituted-2-{4-oxo-2-(2-((3-(2-oxo-2H-chromen-3-yl)-1-(4-phenylthiazol-2-yl)-1H-pyrazol-4-yl)methylene)hydrazineyl)thiazol-5(4H)-ylidene}acetate (5a-h) were synthesized and assessed for their cytotoxic potential against the liver cancer cell lines Huh-7 and HepG-2. Among these, compounds 5d and 5g demonstrated notable antiproliferative effects, which were benchmarked against the standard drug doxorubicin. To further understand the mechanisms behind their antiproliferative activity, compounds 5d and 5g were investigated for their impact on the cell cycle and their ability to induce apoptosis. They were found to induce significant cellular cycle arrest at the G1 phase. Besides, they potentially enhanced the cellular late apoptosis and reduced the cellular viability. In consent with the apoptosis results, compounds 5d and 5g displayed significant potential autophagic induction against the studied cancer cell lines. Further, both compounds 5d and 5g showed strong interactions with the VEGFR-2 receptor when they were studied using molecular docking. The ADMET prediction indicated that these bioactive compounds have the potential to serve as effective to fight liver cancer.
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Affiliation(s)
- Wafa A Bawazir
- Chemistry Department, Faculty of Science, King Abdulaziz University Jeddah Saudi Arabia
| | - Tarik E Ali
- Central Labs, King Khalid University AlQuraa Abha Saudi Arabia
- Department of Chemistry, Faculty of Science, King Khalid University AlQuraa Abha Saudi Arabia
| | - Ayat K Alsolimani
- Department of Chemistry, Faculty of Science, King Khalid University AlQuraa Abha Saudi Arabia
| | - Mohammed A Assiri
- Department of Chemistry, Faculty of Science, King Khalid University AlQuraa Abha Saudi Arabia
| | - Ali A Shati
- Department of Biology, Faculty of Science, King Khalid University AlQuraa Abha Saudi Arabia
| | - Mohammad Y Alfaifi
- Department of Biology, Faculty of Science, King Khalid University AlQuraa Abha Saudi Arabia
| | - Serag E I Elbehairi
- Department of Biology, Faculty of Science, King Khalid University AlQuraa Abha Saudi Arabia
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Kang Q, He L, Zhang Y, Zhong Z, Tan W. Immune-inflammatory modulation by natural products derived from edible and medicinal herbs used in Chinese classical prescriptions. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 130:155684. [PMID: 38788391 DOI: 10.1016/j.phymed.2024.155684] [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: 11/17/2023] [Revised: 01/29/2024] [Accepted: 04/24/2024] [Indexed: 05/26/2024]
Abstract
BACKGROUND Edible and medicinal herbs1 (EMHs) refer to a class of substances with dual attribution of food and medicine. These substances are traditionally used as food and also listed in many international pharmacopoeias, including the European Pharmacopoeia, the United States Pharmacopoeia, and the Chinese Pharmacopoeia. Some classical formulas that are widely used in traditional Chinese medicine include a series of EMHs, which have been shown to be effective with obvious characteristics and advantages. Notably, these EMHs and Chinese classical prescriptions2 (CCPs) have also attracted attention in international herbal medicine research because of their low toxicity and high efficiency as well as the rich body of experience for their long-term clinical use. PURPOSE Our purpose is to explore the potential therapeutic effect of EMHs with immune-inflammatory modulation for the study of modern cancer drugs. STUDY DESIGN In the present study, we present a detailed account of some EMHs used in CCPs that have shown considerable research potential in studies exploring modern drugs with immune-inflammatory modulation. METHODS Approximately 500 publications in the past 30 years were collected from PubMed, Web of Science and ScienceDirect using the keywords, such as natural products, edible and medicinal herbs, Chinese medicine, classical prescription, immune-inflammatory, tumor microenvironment and some related synonyms. The active ingredients instead of herbal extracts or botanical mixtures were focused on and the research conducted over the past decade were discussed emphatically and analyzed comprehensively. RESULTS More than ten natural products derived from EMHs used in CCPs are discussed and their immune-inflammatory modulation activities, including enhancing antitumor immunity, regulating inflammatory signaling pathways, lowering the proportion of immunosuppressive cells, inhibiting the secretion of proinflammatory cytokines, immunosuppressive factors, and inflammatory mediators, are summarized. CONCLUSION Our findings demonstrate the immune-inflammatory modulating role of those EMHs used in CCPs and provide new ideas for cancer treatment in clinical settings.
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Affiliation(s)
- Qianming Kang
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China
| | - Luying He
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China
| | - Yang Zhang
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China
| | - Zhangfeng Zhong
- Macao Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR 999078, China.
| | - Wen Tan
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
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Jiménez DJ, Javed A, Rubio-Tomás T, Seye-Loum N, Barceló C. Clinical and Preclinical Targeting of Oncogenic Pathways in PDAC: Targeted Therapeutic Approaches for the Deadliest Cancer. Int J Mol Sci 2024; 25:2860. [PMID: 38474109 DOI: 10.3390/ijms25052860] [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: 12/21/2023] [Revised: 01/22/2024] [Accepted: 01/30/2024] [Indexed: 03/14/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death worldwide. It is commonly diagnosed in advanced stages and therapeutic interventions are typically constrained to systemic chemotherapy, which yields only modest clinical outcomes. In this review, we examine recent developments in targeted therapy tailored to address distinct molecular pathway alteration required for PDAC. Our review delineates the principal signaling pathways and molecular mechanisms implicated in the initiation and progression of PDAC. Subsequently, we provide an overview of prevailing guidelines, ongoing investigations, and prospective research trajectories related to targeted therapeutic interventions, drawing insights from randomized clinical trials and other pertinent studies. This review focus on a comprehensive examination of preclinical and clinical data substantiating the efficacy of these therapeutic modalities, emphasizing the potential of combinatorial regimens and novel therapies to enhance the quality of life for individuals afflicted with PDAC. Lastly, the review delves into the contemporary application and ongoing research endeavors concerning targeted therapy for PDAC. This synthesis serves to bridge the molecular elucidation of PDAC with its clinical implications, the evolution of innovative therapeutic strategies, and the changing landscape of treatment approaches.
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Affiliation(s)
- Diego J Jiménez
- Translational Pancreatic Cancer Oncogenesis Group, Health Research Institute of the Balearic Islands (IdISBa), Hospital Universitari Son Espases, 07120 Palma de Mallorca, Spain
| | - Aadil Javed
- Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Teresa Rubio-Tomás
- School of Medicine, University of Crete, 70013 Herakleion, Crete, Greece
| | - Ndioba Seye-Loum
- Translational Pancreatic Cancer Oncogenesis Group, Health Research Institute of the Balearic Islands (IdISBa), Hospital Universitari Son Espases, 07120 Palma de Mallorca, Spain
| | - Carles Barceló
- Translational Pancreatic Cancer Oncogenesis Group, Health Research Institute of the Balearic Islands (IdISBa), Hospital Universitari Son Espases, 07120 Palma de Mallorca, Spain
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Silnitsky S, Rubin SJS, Zerihun M, Qvit N. An Update on Protein Kinases as Therapeutic Targets-Part I: Protein Kinase C Activation and Its Role in Cancer and Cardiovascular Diseases. Int J Mol Sci 2023; 24:17600. [PMID: 38139428 PMCID: PMC10743896 DOI: 10.3390/ijms242417600] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 12/10/2023] [Accepted: 12/12/2023] [Indexed: 12/24/2023] Open
Abstract
Protein kinases are one of the most significant drug targets in the human proteome, historically harnessed for the treatment of cancer, cardiovascular disease, and a growing number of other conditions, including autoimmune and inflammatory processes. Since the approval of the first kinase inhibitors in the late 1990s and early 2000s, the field has grown exponentially, comprising 98 approved therapeutics to date, 37 of which were approved between 2016 and 2021. While many of these small-molecule protein kinase inhibitors that interact orthosterically with the protein kinase ATP binding pocket have been massively successful for oncological indications, their poor selectively for protein kinase isozymes have limited them due to toxicities in their application to other disease spaces. Thus, recent attention has turned to the use of alternative allosteric binding mechanisms and improved drug platforms such as modified peptides to design protein kinase modulators with enhanced selectivity and other pharmacological properties. Herein we review the role of different protein kinase C (PKC) isoforms in cancer and cardiovascular disease, with particular attention to PKC-family inhibitors. We discuss translational examples and carefully consider the advantages and limitations of each compound (Part I). We also discuss the recent advances in the field of protein kinase modulators, leverage molecular docking to model inhibitor-kinase interactions, and propose mechanisms of action that will aid in the design of next-generation protein kinase modulators (Part II).
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Affiliation(s)
- Shmuel Silnitsky
- The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Henrietta Szold St. 8, Safed 1311502, Israel; (S.S.); (M.Z.)
| | - Samuel J. S. Rubin
- Department of Medicine, School of Medicine, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA;
| | - Mulate Zerihun
- The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Henrietta Szold St. 8, Safed 1311502, Israel; (S.S.); (M.Z.)
| | - Nir Qvit
- The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Henrietta Szold St. 8, Safed 1311502, Israel; (S.S.); (M.Z.)
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Li Y, Liu W, Xu J, Guo Y. Chlorahololide D, a Lindenane-Type Sesquiterpenoid Dimer from Chloranthus holostegius Suppressing Breast Cancer Progression. Molecules 2023; 28:7070. [PMID: 37894550 PMCID: PMC10608938 DOI: 10.3390/molecules28207070] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 10/08/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
Aimed at discovering small molecules as anticancer drugs or lead compounds from plants, a lindenane-type sesquiterpene dimer, chlorahololide D, was isolated from Chloranthus holostegius. The literature review showed that there were few reports on the antitumor effects and mechanisms of chlorahololide D. Our biological assay suggested that chlorahololide D blocked the growth and triggered apoptosis of MCF-7 cells by stimulating the reactive oxygen species (ROS) levels and arresting the cell cycle at the G2 stage. Further mechanism exploration suggested that chlorahololide D regulated apoptosis-related proteins Bcl-2 and Bax. Moreover, chlorahololide D inhibited cell migration by regulating the FAK signaling pathway. In the zebrafish xenograft model, chlorahololide D was observed to suppress tumor proliferation and migration significantly. Considering the crucial function of angiogenesis in tumor development, the anti-angiogenesis of chlorahololide D was also investigated. All of the research preliminarily revealed that chlorahololide D could become an anti-breast cancer drug.
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Affiliation(s)
- Ying Li
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China; (Y.L.); (W.L.)
| | - Wenhui Liu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China; (Y.L.); (W.L.)
| | - Jing Xu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China; (Y.L.); (W.L.)
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China
| | - Yuanqiang Guo
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China; (Y.L.); (W.L.)
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Baral B, Panigrahi B, Kar A, Tulsiyan KD, Suryakant U, Mandal D, Subudhi U. Peptide nanostructures-based delivery of DNA nanomaterial therapeutics for regulating gene expression. MOLECULAR THERAPY. NUCLEIC ACIDS 2023; 33:493-510. [PMID: 37583574 PMCID: PMC10424151 DOI: 10.1016/j.omtn.2023.07.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 07/14/2023] [Indexed: 08/17/2023]
Abstract
Self-assembled branched DNA (bDNA) nanomaterials have exhibited their functionality in various biomedical and diagnostic applications. However, the anionic cellular membrane has restricted the movement of bDNA nanostructures. Recently, amphiphilic peptides have been investigated as cationic delivery agents for nucleic acids. Herein, we demonstrate a strategy for delivering functional bDNA nanomaterials into mammalian cells using self-assembled linear peptides. In this study, antisense oligonucleotides of vascular endothelial growth factor (VEGF) were inserted in the overhangs of bDNAs. Novel linear peptides have been synthesized and the peptide-bound bDNA complex formation was examined using various biophysical experiments. Interestingly, the W4R4-bound bDNAs were found to be exceptionally stable against DNase I compared to other complexes. The delivery of fluorescent-labeled bDNAs into the mammalian cells confirmed the potential of peptide transporters. Furthermore, the functional efficacy of the peptide-bound bDNAs has been examined through RT-PCR and western blot analysis. The observed results revealed that W4R4 peptides exhibited excellent internalization of antisense bDNAs and significantly suppressed (3- to 4-fold) the transcripts and translated product of VEGF compared to the control. In summary, the results highlight the potential use of peptide-based nanocarrier for delivering bDNA nanostructures to regulate the gene expression in cell lines.
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Affiliation(s)
- Bineeth Baral
- DNA Nanotechnology & Application Laboratory, Environment & Sustainability Department, CSIR-Institute of Minerals & Materials Technology, Bhubaneswar 751013, Odisha, India
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Bijayananda Panigrahi
- School of Biotechnology, Kalinga Institute of Industrial Technology Deemed to be University, Bhubaneswar 751024, Odisha, India
- Biopioneer Private Limited, Bhubaneswar 751024, Odisha, India
| | - Avishek Kar
- DNA Nanotechnology & Application Laboratory, Environment & Sustainability Department, CSIR-Institute of Minerals & Materials Technology, Bhubaneswar 751013, Odisha, India
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Kiran D. Tulsiyan
- School of Chemical Sciences, National Institute of Science Education & Research, Bhubaneswar 752050, India
- Homi Bhaba National Institute, Mumbai 400094, India
| | - Uday Suryakant
- School of Biotechnology, Kalinga Institute of Industrial Technology Deemed to be University, Bhubaneswar 751024, Odisha, India
| | - Dindyal Mandal
- School of Biotechnology, Kalinga Institute of Industrial Technology Deemed to be University, Bhubaneswar 751024, Odisha, India
| | - Umakanta Subudhi
- DNA Nanotechnology & Application Laboratory, Environment & Sustainability Department, CSIR-Institute of Minerals & Materials Technology, Bhubaneswar 751013, Odisha, India
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002, India
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Yun HD, Goel Y, Gupta K. Crosstalk of Mast Cells and Natural Killer Cells with Neurons in Chemotherapy-Induced Peripheral Neuropathy. Int J Mol Sci 2023; 24:12543. [PMID: 37628724 PMCID: PMC10454469 DOI: 10.3390/ijms241612543] [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: 07/11/2023] [Revised: 08/04/2023] [Accepted: 08/05/2023] [Indexed: 08/27/2023] Open
Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a major comorbidity of cancer. Multiple clinical interventions have been studied to effectively treat CIPN, but the results have been disappointing, with no or little efficacy. Hence, understanding the pathophysiology of CIPN is critical to improving the quality of life and clinical outcomes of cancer patients. Although various mechanisms of CIPN have been described in neuropathic anti-cancer agents, the neuroinflammatory process involving cytotoxic/proinflammatory immune cells remains underexamined. While mast cells (MCs) and natural killer (NK) cells are the key innate immune compartments implicated in the pathogenesis of peripheral neuropathy, their role in CIPN has remained under-appreciated. Moreover, the biology of proinflammatory cytokines associated with MCs and NK cells in CIPN is particularly under-evaluated. In this review, we will focus on the interactions between MCs, NK cells, and neuronal structure and their communications via proinflammatory cytokines, including TNFα, IL-1β, and IL-6, in peripheral neuropathy in association with tumor immunology. This review will help lay the foundation to investigate MCs, NK cells, and cytokines to advance future therapeutic strategies for CIPN.
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Affiliation(s)
- Hyun Don Yun
- Hematology, Oncology, Veterans Affairs Long Beach Healthcare System, Long Beach, CA 90822, USA
- Division of Hematology, Oncology, Department of Medicine, School of Medicine, University of California, Irvine, CA 92617, USA; (Y.G.); (K.G.)
| | - Yugal Goel
- Division of Hematology, Oncology, Department of Medicine, School of Medicine, University of California, Irvine, CA 92617, USA; (Y.G.); (K.G.)
| | - Kalpna Gupta
- Division of Hematology, Oncology, Department of Medicine, School of Medicine, University of California, Irvine, CA 92617, USA; (Y.G.); (K.G.)
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12
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Soliman DH, Nafie MS. Design, synthesis, and docking studies of novel pyrazole-based scaffolds and their evaluation as VEGFR2 inhibitors in the treatment of prostate cancer. RSC Adv 2023; 13:20443-20456. [PMID: 37435371 PMCID: PMC10331375 DOI: 10.1039/d3ra02579a] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 06/28/2023] [Indexed: 07/13/2023] Open
Abstract
Since VEGFR-2 plays a crucial role in tumor growth, angiogenesis, and metastasis, it is a prospective target for cancer treatment. In this work, a series of 3-phenyl-4-(2-substituted phenylhydrazono)-1H-pyrazol-5(4H)-ones (3a-l) were synthesized and investigated for their cytotoxicity against the PC-3 human cancer cell line compared to Doxorubicin and Sorafenib as reference drugs. Two compounds 3a and 3i showed comparable cytotoxic activity with IC50 values of 1.22 and 1.24 μM compared to the reference drugs (IC50 = 0.932, 1.13 μM). Compound 3i was found to be the most effective VEGFR-2 inhibitor using in vitro testing of the synthesized compounds, with nearly 3-fold higher activity than Sorafenib (30 nM), with IC50 8.93 nM. Compound 3i significantly stimulated total apoptotic prostate cancer cell death 55.2-fold (34.26% compared to 0.62% for the control) arresting the cell cycle at the S-phase. The genes involved in apoptosis were also impacted, with proapoptotic genes being upregulated and antiapoptotic Bcl-2 being downregulated. These results were supported by docking studies of these two compounds within the active site of the VEGFR2 enzyme. Finally, in vivo, the study revealed the potentiality of compound 3i to inhibit tumor proliferation by 49.8% reducing the tumor weight from 234.6 mg in untreated mice to 83.2 mg. Therefore, 3i could be a promising anti-prostate cancer agent.
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Affiliation(s)
- Dalia H Soliman
- Department of Pharmaceutical Medicinal Chemistry and Drug Design, Faculty of Pharmacy (Girls), Al-Azhar University Egypt
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University Badr City Cairo Egypt
| | - Mohamed S Nafie
- Department of Chemistry (Biochemistry Program), Faculty of Science, Suez Canal University Ismailia 41522 Egypt
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13
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Chen B, Jin W. A comprehensive review of stroke-related signaling pathways and treatment in western medicine and traditional Chinese medicine. Front Neurosci 2023; 17:1200061. [PMID: 37351420 PMCID: PMC10282194 DOI: 10.3389/fnins.2023.1200061] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 05/19/2023] [Indexed: 06/24/2023] Open
Abstract
This review provides insight into the complex network of signaling pathways and mechanisms involved in stroke pathophysiology. It summarizes the historical progress of stroke-related signaling pathways, identifying potential interactions between them and emphasizing that stroke is a complex network disease. Of particular interest are the Hippo signaling pathway and ferroptosis signaling pathway, which remain understudied areas of research, and are therefore a focus of the review. The involvement of multiple signaling pathways, including Sonic Hedgehog (SHH), nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE), hypoxia-inducible factor-1α (HIF-1α), PI3K/AKT, JAK/STAT, and AMPK in pathophysiological mechanisms such as oxidative stress and apoptosis, highlights the complexity of stroke. The review also delves into the details of traditional Chinese medicine (TCM) therapies such as Rehmanniae and Astragalus, providing an analysis of the recent status of western medicine in the treatment of stroke and the advantages and disadvantages of TCM and western medicine in stroke treatment. The review proposes that since stroke is a network disease, TCM has the potential and advantages of a multi-target and multi-pathway mechanism of action in the treatment of stroke. Therefore, it is suggested that future research should explore more treasures of TCM and develop new therapies from the perspective of stroke as a network disease.
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Affiliation(s)
- Binhao Chen
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Weifeng Jin
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, China
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14
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Chen J, Shen Y, Shao X, Wu W. An emerging role of inflammasomes in spinal cord injury and spinal cord tumor. Front Immunol 2023; 14:1119591. [PMID: 36969234 PMCID: PMC10033975 DOI: 10.3389/fimmu.2023.1119591] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 02/27/2023] [Indexed: 03/11/2023] Open
Abstract
Spinal cord injury (SCI) and spinal cord tumor are devastating events causing structural and functional impairment of the spinal cord and resulting in high morbidity and mortality; these lead to a psychological burden and financial pressure on the patient. These spinal cord damages likely disrupt sensory, motor, and autonomic functions. Unfortunately, the optimal treatment of and spinal cord tumors is limited, and the molecular mechanisms underlying these disorders are unclear. The role of the inflammasome in neuroinflammation in diverse diseases is becoming increasingly important. The inflammasome is an intracellular multiprotein complex and participates in the activation of caspase-1 and the secretion of pro-inflammatory cytokines such as interleukin (IL)-1β and IL-18. The inflammasome in the spinal cord is involved in the stimulation of immune-inflammatory responses through the release of pro-inflammatory cytokines, thereby mediating further spinal cord damage. In this review, we highlight the role of inflammasomes in SCI and spinal cord tumors. Targeting inflammasomes is a promising therapeutic strategy for the treatment of SCI and spinal cord tumors.
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15
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Hosseinkhani H, Domb AJ, Sharifzadeh G, Nahum V. Gene Therapy for Regenerative Medicine. Pharmaceutics 2023; 15:856. [PMID: 36986717 PMCID: PMC10057434 DOI: 10.3390/pharmaceutics15030856] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 02/24/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023] Open
Abstract
The development of biological methods over the past decade has stimulated great interest in the possibility to regenerate human tissues. Advances in stem cell research, gene therapy, and tissue engineering have accelerated the technology in tissue and organ regeneration. However, despite significant progress in this area, there are still several technical issues that must be addressed, especially in the clinical use of gene therapy. The aims of gene therapy include utilising cells to produce a suitable protein, silencing over-producing proteins, and genetically modifying and repairing cell functions that may affect disease conditions. While most current gene therapy clinical trials are based on cell- and viral-mediated approaches, non-viral gene transfection agents are emerging as potentially safe and effective in the treatment of a wide variety of genetic and acquired diseases. Gene therapy based on viral vectors may induce pathogenicity and immunogenicity. Therefore, significant efforts are being invested in non-viral vectors to enhance their efficiency to a level comparable to the viral vector. Non-viral technologies consist of plasmid-based expression systems containing a gene encoding, a therapeutic protein, and synthetic gene delivery systems. One possible approach to enhance non-viral vector ability or to be an alternative to viral vectors would be to use tissue engineering technology for regenerative medicine therapy. This review provides a critical view of gene therapy with a major focus on the development of regenerative medicine technologies to control the in vivo location and function of administered genes.
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Affiliation(s)
- Hossein Hosseinkhani
- Innovation Center for Advanced Technology, Matrix, Inc., New York, NY 10019, USA
| | - Abraham J. Domb
- The Center for Nanoscience and Nanotechnology, Alex Grass Center for Drug Design and Synthesis and Cannabinoids Research, School of Pharmacy, Faculty of Medicine, Institute of Drug Research, The Hebrew University of Jerusalem, Jerusalem 91120, Israel
| | - Ghorbanali Sharifzadeh
- Department of Polymer Engineering, School of Chemical Engineering, Universiti Teknologi Malaysia, Skudai 81310, Johor, Malaysia
| | - Victoria Nahum
- The Center for Nanoscience and Nanotechnology, Alex Grass Center for Drug Design and Synthesis and Cannabinoids Research, School of Pharmacy, Faculty of Medicine, Institute of Drug Research, The Hebrew University of Jerusalem, Jerusalem 91120, Israel
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16
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Wieser V, Tsibulak I, Reimer DU, Zeimet AG, Fiegl H, Hackl H, Marth C. An angiogenic tumor phenotype predicts poor prognosis in ovarian cancer. Gynecol Oncol 2023; 170:290-299. [PMID: 36758419 DOI: 10.1016/j.ygyno.2023.01.034] [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: 11/09/2022] [Revised: 01/26/2023] [Accepted: 01/27/2023] [Indexed: 02/09/2023]
Abstract
OBJECTIVE Epithelial ovarian cancer (OC) is the deadliest gynecological malignancy worldwide. Blocking angiogenesis with bevacizumab, an antibody targeting vascular endothelial growth factor (VEGF), shows efficacy in different lines of OC therapy. This study investigates the clinical impact of tumoral expression of angiogenesis-related genes and their association with bevacizumab response in OC in retrospective analysis of three independent cohorts. METHODS mRNA expression of seven angiogenic genes (VEGF, VEGFR2, PDGFA, PDGFB, PDGFRA, PDGFRB, KIT) was quantified in an inception OC cohort (n = 195) and a transcriptional tumor angiogenesis score from 0 to 3 was established and linked to progression-free survival (PFS) and overall survival (OS). This score was corroborated in an independent publicly available cohort from The Cancer Genome Atlas (TCGA, n = 582) and prediction of therapeutic efficacy of bevacizumab by the angiogenesis score was analyzed in the Gene Expression Omnibus (GEO) dataset GSE140082 (n = 380) from the ICON7-trial. RESULTS The tumor angiogenesis score prognosticated PFS and OS in patients with OC from the inception cohort (p < 0.001, respectively). Tumoral PDGFA expression (PFS: HR 2.46, p = 0.005; OS: HR 2.26, p = 0.011) and a high tumoral transcriptional angiogenesis score (PFS: HR 1.41, p = 0.018) were identified as independent predictors of clinical outcome. The transcriptional angiogenesis score exhibited a significant though smaller effect size on PFS in the TCGA cohort. However, in the ICON7-trial, the angiogenesis score was not associated with benefit of bevacizumab treatment. CONCLUSIONS Our study indicates that tumoral expression of angiogenic genes is unfavorable in OC. The established score could be used to identify patients who respond to targeted angiogenic therapies, a concept that warrants prospective controlled clinical trials.
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Affiliation(s)
- Verena Wieser
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
| | - Irina Tsibulak
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Daniel Uwe Reimer
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Alain Gustave Zeimet
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Heidelinde Fiegl
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Hubert Hackl
- Biocenter, Institute of Bioinformatics, Medical University Innsbruck, 6020 Innsbruck, Austria
| | - Christian Marth
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, 6020 Innsbruck, Austria
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17
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Xu M, Chen X, Yu Z, Li X. Receptors that bind to PEDF and their therapeutic roles in retinal diseases. Front Endocrinol (Lausanne) 2023; 14:1116136. [PMID: 37139333 PMCID: PMC10149954 DOI: 10.3389/fendo.2023.1116136] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 04/04/2023] [Indexed: 05/05/2023] Open
Abstract
Retinal neovascular, neurodegenerative, and inflammatory diseases represented by diabetic retinopathy are the main types of blinding eye disorders that continually cause the increased burden worldwide. Pigment epithelium-derived factor (PEDF) is an endogenous factor with multiple effects including neurotrophic activity, anti-angiogenesis, anti-tumorigenesis, and anti-inflammatory activity. PEDF activity depends on the interaction with the proteins on the cell surface. At present, seven independent receptors, including adipose triglyceride lipase, laminin receptor, lipoprotein receptor-related protein, plexin domain-containing 1, plexin domain-containing 2, F1-ATP synthase, and vascular endothelial growth factor receptor 2, have been demonstrated and confirmed to be high affinity receptors for PEDF. Understanding the interactions between PEDF and PEDF receptors, their roles in normal cellular metabolism and the response the initiate in disease will be accommodating for elucidating the ways in which inflammation, angiogenesis, and neurodegeneration exacerbate disease pathology. In this review, we firstly introduce PEDF receptors comprehensively, focusing particularly on their expression pattern, ligands, related diseases, and signal transduction pathways, respectively. We also discuss the interactive ways of PEDF and receptors to expand the prospective understanding of PEDF receptors in the diagnosis and treatment of retinal diseases.
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18
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Jiang T, Chen Y, Gu X, Miao M, Hu D, Zhou H, Chen J, Teichmann AT, Yang Y. Review of the Potential Therapeutic Effects and Molecular Mechanisms of Resveratrol on Endometriosis. Int J Womens Health 2023; 15:741-763. [PMID: 37200624 PMCID: PMC10187648 DOI: 10.2147/ijwh.s404660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 04/08/2023] [Indexed: 05/20/2023] Open
Abstract
Endometriosis is a hormone-dependent inflammatory disease characterized by the existence of endometrial tissues outside the uterine cavity. Pharmacotherapy and surgery are the current dominant management options for endometriosis. The greater incidence of recurrence and reoperation after surgical treatment as well as the adverse effects of medical approaches predispose patients to potential limitations for their long-term usage. Consequently, it is essential to explore novel supplementary and alternative drugs to ameliorate the therapeutic outcomes of endometriotic patients. Resveratrol is a phenolic compound that has attracted increasing interest from many researchers due to its pleiotropic biological activities. Here, we review the possible therapeutic efficacies and molecular mechanisms of resveratrol against endometriosis based on in vitro, animal, and clinical studies. The potential mechanisms of resveratrol include anti-proliferative, pro-apoptotic, anti-angiogenic, anti-oxidative stress, anti-invasive and anti-adhesive effects, thereby suggesting that resveratrol is a promising candidate for endometriosis. Because most studies have investigated the effectiveness of resveratrol on endometriosis via in vitro trials and/or experimental animal models, further high-quality clinical trials should be undertaken to comprehensively estimate the clinical application feasibility of resveratrol on endometriosis.
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Affiliation(s)
- Tao Jiang
- Sichuan Provincial Center for Gynaecology and Breast Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China
| | - Yuan Chen
- Sichuan Provincial Center for Gynaecology and Breast Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China
| | - Xia Gu
- Sichuan Provincial Center for Gynaecology and Breast Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China
- Academician (Expert) Workstation of Sichuan Province, Luzhou, 646000, People’s Republic of China
| | - Mengyue Miao
- Sichuan Provincial Center for Gynaecology and Breast Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China
| | - Daifeng Hu
- Sichuan Provincial Center for Gynaecology and Breast Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China
| | - Hui Zhou
- Sichuan Provincial Center for Gynaecology and Breast Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China
| | - Jing Chen
- Reproductive Medicine Center, The Second People’s Hospital of Yibin, Yibin, 644000, People’s Republic of China
| | - Alexander Tobias Teichmann
- Sichuan Provincial Center for Gynaecology and Breast Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China
- Correspondence: Alexander Tobias Teichmann; Youzhe Yang, The Affiliated Hospital of Southwest Medical University, No. 25 Taiping Street, Jiangyang District, Luzhou, 646000, People’s Republic of China, Email ;
| | - Youzhe Yang
- Sichuan Provincial Center for Gynaecology and Breast Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China
- Academician (Expert) Workstation of Sichuan Province, Luzhou, 646000, People’s Republic of China
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19
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Abdelsalam EA, Abd El-Hafeez AA, Eldehna WM, El Hassab MA, Marzouk HMM, Elaasser MM, Abou Taleb NA, Amin KM, Abdel-Aziz HA, Ghosh P, Hammad SF. Discovery of novel thiazolyl-pyrazolines as dual EGFR and VEGFR-2 inhibitors endowed with in vitro antitumor activity towards non-small lung cancer. J Enzyme Inhib Med Chem 2022; 37:2265-2282. [PMID: 36000167 PMCID: PMC9415638 DOI: 10.1080/14756366.2022.2104841] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
New series of thiazolyl-pyrazoline derivatives (7a–7d, 10a–10d and 13a–13f) have been synthesised and assessed for their potential EGFR and VEGFR-2 inhibitory activities. Compounds 10b and 10d exerted potent and selective inhibitory activity towards the two receptor tyrosine kinases; EGFR (IC50 = 40.7 ± 1.0 and 32.5 ± 2.2 nM, respectively) and VEGFR-2 (IC50 = 78.4 ± 1.5 and 43.0 ± 2.4 nM, respectively). The best anti-proliferative activity for the examined thiazolyl-pyrazolines was observed against the non-small lung cancer cells (NSCLC). Compounds 10b and 10d displayed pronounced efficacy against A549 (IC50 = 4.2 and 2.9 µM, respectively) and H441 cell lines (IC50 = 4.8 and 3.8 µM, respectively). Moreover, our results indicated that 10b and 10d were much more effective towards EGFR-mutated NSCLC cell lines (NCI-H1650 and NCI-H1975 cells) than gefitinib. Finally, compounds 10b and 10d induce G2/M cell cycle arrest and apoptosis and inhibit migration in A549 cancerous cells.
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Affiliation(s)
- Esraa A Abdelsalam
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Cairo, Egypt
| | - Amer Ali Abd El-Hafeez
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.,Pharmacology and Experimental Oncology Unit, Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Wagdy M Eldehna
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.,School of Biotechnology, Badr University in Cairo, Badr City, Cairo, Egypt
| | - Mahmoud A El Hassab
- Department of Medicinal Chemistry, Faculty of Pharmacy, King Salman International University (KSIU), South Sinai, Egypt
| | - Hala Mohamed M Marzouk
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.,Department of Biochemistry, Faculty of Medicine, Minia University, El-Minia, Egypt
| | - Mahmoud M Elaasser
- The Regional Center for Mycology and Biotechnology, Al-Azhar University, Cairo, Egypt
| | - Nageh A Abou Taleb
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Cairo, Egypt
| | - Kamilia M Amin
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Hatem A Abdel-Aziz
- Department of Applied Organic Chemistry, National Research Centre, Dokki, Giza, Egypt
| | - Pradipta Ghosh
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.,Department of Medicine, University of California San Diego, La Jolla, CA, USA.,Moores Comprehensive Cancer Center, University of California San Diego, La Jolla, CA, USA.,Veterans Affairs Medical Center, La Jolla, CA, USA
| | - Sherif F Hammad
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Cairo, Egypt.,PharmD Program and Basic and Applied Sciences Institute, Egypt-Japan University of Science and Technology (E-JUST), Alexandria, Egypt
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20
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Zhang S, Li Y, Li Z, Liu W, Zhang H, Ohizumi Y, Nakajima A, Xu J, Guo Y. Structure, anti-tumor activity, and potential anti-tumor mechanism of a fungus polysaccharide from Fomes officinalis. Carbohydr Polym 2022; 295:119794. [DOI: 10.1016/j.carbpol.2022.119794] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 06/21/2022] [Accepted: 06/26/2022] [Indexed: 12/12/2022]
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21
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Hou CY, Ma CY, Lin YJ, Huang CL, Wang HD, Yuh CH. WNK1–OSR1 Signaling Regulates Angiogenesis-Mediated Metastasis towards Developing a Combinatorial Anti-Cancer Strategy. Int J Mol Sci 2022; 23:ijms232012100. [PMID: 36292952 PMCID: PMC9602556 DOI: 10.3390/ijms232012100] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 10/07/2022] [Accepted: 10/08/2022] [Indexed: 12/03/2022] Open
Abstract
Lysine-deficient protein kinase-1 (WNK1) is critical for both embryonic angiogenesis and tumor-induced angiogenesis. However, the downstream effectors of WNK1 during these processes remain ambiguous. In this study, we identified that oxidative stress responsive 1b (osr1b) is upregulated in endothelial cells in both embryonic and tumor-induced angiogenesis in zebrafish, accompanied by downregulation of protein phosphatase 2A (pp2a) subunit ppp2r1bb. In addition, wnk1a and osr1b are upregulated in two liver cancer transgenic fish models: [tert x p53−/−] and [HBx,src,p53−/−,RPIA], while ppp2r1bb is downregulated in [tert x p53−/−]. Furthermore, using HUVEC endothelial cells co-cultured with HepG2 hepatoma cells, we confirmed that WNK1 plays a critical role in the induction of hepatoma cell migration in both endothelial cells and hepatoma cells. Moreover, overexpression of OSR1 can rescue the reduced cell migration caused by shWNK1 knockdown in HUVEC cells, indicating OSR1 is downstream of WNK1 in endothelial cells promoting hepatoma cell migration. Overexpression of PPP2R1A can rescue the increased cell migration caused by WNK1 overexpression in HepG2, indicating that PPP2R1A is a downstream effector in hepatoma. The combinatorial treatment with WNK1 inhibitor (WNK463) and OSR1 inhibitor (Rafoxanide) plus oligo-fucoidan via oral gavage to feed [HBx,src,p53−/−,RPIA] transgenic fish exhibits much more significant anticancer efficacy than Regorafenib for advanced HCC. Importantly, oligo-fucoidan can reduce the cell senescence marker-IL-1β expression. Furthermore, oligo-fucoidan reduces the increased cell senescence-associated β-galactosidase activity in tert transgenic fish treated with WNK1-OSR1 inhibitors. Our results reveal the WNK1–OSR1–PPP2R1A axis plays a critical role in both endothelial and hepatoma cells during tumor-induced angiogenesis promoting cancer cell migration. By in vitro and in vivo experiments, we further uncover the molecular mechanisms of WNK1 and its downstream effectors during tumor-induced angiogenesis. Targeting WNK1–OSR1-mediated anti-angiogenesis and anti-cancer activity, the undesired inflammation response caused by inhibiting WNK1–OSR1 can be attenuated by the combination therapy with oligo-fucoidan and may improve the efficacy.
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Affiliation(s)
- Chia-Ying Hou
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan
- Institute of Biotechnology, National Tsing Hua University, Hsinchu 300044, Taiwan
| | - Chung-Yung Ma
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan
| | - Yu-Ju Lin
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan
| | - Chou-Long Huang
- Division of Nephrology, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Horng-Dar Wang
- Institute of Biotechnology, National Tsing Hua University, Hsinchu 300044, Taiwan
- Institute of Systems Neuroscience, National Tsing Hua University, Hsinchu 300044, Taiwan
- Department of Life Science, National Tsing Hua University, Hsinchu 300044, Taiwan
- Correspondence: (H.-D.W.); (C.-H.Y.); Tel.: +886-3-5742470 (H.-D.W.); +886-37-206166 (ext. 35338) (C.-H.Y.)
| | - Chiou-Hwa Yuh
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan
- Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 300044, Taiwan
- Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 30010, Taiwan
- Ph.D. Program in Environmental and Occupational Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Correspondence: (H.-D.W.); (C.-H.Y.); Tel.: +886-3-5742470 (H.-D.W.); +886-37-206166 (ext. 35338) (C.-H.Y.)
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22
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Mui AW, Lee AW, Ng W, Lee VH, Vardhanabhuti V, Man SS, Chua DT, Guan X. Correlations of tumour permeability parameters with apparent diffusion coefficient in nasopharyngeal carcinoma. Phys Imaging Radiat Oncol 2022; 24:30-35. [PMID: 36148154 PMCID: PMC9485900 DOI: 10.1016/j.phro.2022.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 09/06/2022] [Accepted: 09/06/2022] [Indexed: 11/03/2022] Open
Abstract
Vascular permeability is associated with diffusability in nasopharyngeal tumour. Both influx and reflux rates have inverse linear correlations with ADC. Reflux rate has the strongest inverse linear correlation with ADC. Background and Purpose Functional imaging has an established role in therapeutic monitoring of cancer treatments. This study evaluated the correlations of tumour permeability parameters derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and tumour cellularity derived from apparent diffusion coefficient (ADC) in nasopharyngeal carcinoma (NPC). Material and Methods Twenty NPC patients were examined with DCE-MRI and RESOLVE diffusion-weighted MRI (DW-MRI). Tumour permeability parameters were quantitatively measured with Tofts compartment model. Volume transfer constant (Ktrans), volume of extravascular extracellular space (EES) per unit volume of tissue (Ve), and the flux rate constant between EES and plasma (Kep) from DCE-MRI scan were measured. The time-intensity curve was plotted from the 60 dynamic phases of DCE-MRI. The initial area under the curve for the first 60 s of the contrast agent arrival (iAUC60) was also calculated. They were compared with the ADC value derived from DW-MRI with Pearson correlation analyses. Results Among the DCE-MRI permeability parameters, Kep had higher linearity in inverse correlation with ADC value (r = −0.69, p = <0.05). Ktrans (r = −0.60, p=<0.05) and iAUC60 (r = −0.64, p = <0.05) also had significant inverse correlations with ADC. Ve showed a significant positive correlation with ADC (r = 0.63, p = <0.05). Conclusions Nasopharyngeal tumour vascular permeability parameters derived from DCE-MRI scan were correlated linearly with tumour cellularity measured by free water diffusability with ADC. The clinical implementations of these linear correlations in the quantitative assessments of therapeutic response for NPC patients may be worth to further explore.
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Zhang C, Wang H. Accurate treatment of small cell lung cancer: Current progress, new challenges and expectations. Biochim Biophys Acta Rev Cancer 2022; 1877:188798. [PMID: 36096336 DOI: 10.1016/j.bbcan.2022.188798] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 08/19/2022] [Accepted: 09/05/2022] [Indexed: 11/28/2022]
Abstract
Small cell lung cancer (SCLC) is a deadly disease with poor prognosis. Fast growing speed, inclination to metastasis, enrichment in cancer stem cells altogether constitute its aggressive nature. In stark contrast to non-small cell lung cancer (NSCLC) that strides vigorously on the road to precision oncology, SCLC has been on the embryonic path to achieve effective personalized treatments. The survival of patients with SCLC have not been improved greatly, which could be possibly due to our inadequate understanding of genetic alterations of SCLC. Recently, encouraging effects have been observed in patients with SCLC undergoing immunotherapy. However, exciting results have only been observed in a small fraction of patients with SCLC, warranting biomarkers predictive of responses as well as novel therapeutic strategies. In addition, SCLC has previously been viewed to be homogeneous. However, perspectives have been changed thanks to the advances in sequencing techniques and platforms, which unfolds the complex heterogeneity of SCLC both genetically and non-genetically, rendering the treatment of SCLC a further step forward into the precision era. To outline the road of SCLC towards precision oncology, we summarize the progresses and achievements made in precision treatment in SCLC in genomic, transcriptomic, epigenetic, proteomic and metabolic dimensions. Moreover, we conclude relevant therapeutic vulnerabilities in SCLC. Clinically tested drugs and clinical trials have also been demonstrated. Ultimately, we look into the opportunities and challenges ahead to advance the individualized treatment in pursuit of improved survival for patients with SCLC.
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Affiliation(s)
- Chenyue Zhang
- Department of Integrated Therapy, Fudan University Shanghai Cancer Center, Shanghai Medical College, Shanghai, China
| | - Haiyong Wang
- Department of Internal Medicine-Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
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Elebiyo TC, Rotimi D, Evbuomwan IO, Maimako RF, Iyobhebhe M, Ojo OA, Oluba OM, Adeyemi OS. Reassessing vascular endothelial growth factor (VEGF) in anti-angiogenic cancer therapy. Cancer Treat Res Commun 2022; 32:100620. [PMID: 35964475 DOI: 10.1016/j.ctarc.2022.100620] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 06/02/2022] [Accepted: 08/05/2022] [Indexed: 05/23/2023]
Abstract
Vascularization is fundamental to the growth and spread of tumor cells to distant sites. As a consequence, angiogenesis, the sprouting of new blood vessels from existing ones, is a characteristic trait of cancer. In 1971, Judah Folkman postulated that tumour growth is angiogenesis dependent and that by cutting off blood supply, a neoplastic lesion could be potentially starved into remission. Decades of research have been devoted to understanding the role that vascular endothelial growth factor (VEGF) plays in tumor angiogenesis, and it has been identified as a significant pro-angiogenic factor that is frequently overexpressed within a tumor mass. Today, anti-VEGF drugs such as Sunitinib, Sorafenib, Axitinib, Tanibirumab, and Ramucirumab have been approved for the treatment of advanced and metastatic cancers. However, anti-angiogenic therapy has turned out to be more complex than originally thought. The failure of this therapeutic option calls for a reevaluation of VEGF as the major target in anti-angiogenic cancer therapy. The call for reassessment is based on two rationales: first, tumour blood vessels are abnormal, disorganized, and leaky; this not only prevents optimal drug delivery but it also promotes hypoxia and metastasis; secondly, tumour growth or regrowth might be blood vessel dependent and not angiogenesis dependent as tumour cells can acquire blood vessels via non-angiogenic mechanisms. Therefore, a critical assessment of VEGF, VEGFRs, and their inhibitors could glean newer options such as repurposing anti-VEGF drugs as vascular normalizing agents to enhance drug delivery of immune checkpoint inhibitors.
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Affiliation(s)
| | - Damilare Rotimi
- Department of Biochemistry, Landmark University, Omu-Aran, Nigeria
| | | | | | | | - Oluwafemi Adeleke Ojo
- Phytomedicine, Molecular Toxicology, and Computational Biochemistry Research Laboratory (PMTCB-RL), Department of Biochemistry, Bowen University, Iwo, 232101, Nigeria..
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Gomes DA, Joubert AM, Visagie MH. In Vitro Effects of Papaverine on Cell Migration and Vascular Endothelial Growth Factor in Cancer Cell Lines. Int J Mol Sci 2022; 23:4654. [PMID: 35563045 PMCID: PMC9104338 DOI: 10.3390/ijms23094654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 04/21/2022] [Accepted: 04/21/2022] [Indexed: 02/04/2023] Open
Abstract
Papaverine (PPV) is a benzylisoquinoline alkaloid isolated from Papaver somniferum that exerts antiproliferative activity. However, several questions remain regarding the biochemical pathways affected by PPV in tumourigenic cells. In this study, the influence of PPV on cell migration (light microscopy), expression of vascular endothelial growth factor (VEGF) B, VEGF R1, VEGF R2, and phosphorylated focal adhesion kinase (pFAK) were investigated using spectrophotometry in MDA-MB-231-, A549- and DU145 cell lines. The migration assay revealed that, after 48 h, PPV (100 µM) reduced cell migration to 81%, 91%, and 71% in MDA-MB-231-, A549-, and DU145 cells, respectively. VEGF B expression was reduced to 0.79-, 0.71-, and 0.73-fold after 48 h of exposure to PPV in MDA-MB-231-, A549- and DU145 cells, while PPV exposure of 48 h increased VEGF R1 expression in MDA-MB-231- and DU145 cells to 1.38 and 1.46. A fold decrease in VEGF R1 expression was observed in A549 cells to 0.90 after exposure to 150 µM. No statistically significant effects were observed on VEGF R2- and FAK expression after exposure to PPV. This study contributes to the understanding of the effects of a phytomedicinal alkaloid compound in cancer cells and may provide novel approaches to the application of non-addictive alkaloids.
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Affiliation(s)
| | | | - Michelle Helen Visagie
- Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Gezina, Pretoria 0031, South Africa; (D.A.G.); (A.M.J.)
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Singh M, Jindal D, Agarwal V, Pathak D, Sharma M, Pancham P, Mani S, Rachana. New phase therapeutic pursuits for targeted drug delivery in glioblastoma multiforme. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2022; 3:866-888. [PMID: 36654821 PMCID: PMC9834280 DOI: 10.37349/etat.2022.00118] [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: 06/11/2022] [Accepted: 08/19/2022] [Indexed: 12/31/2022] Open
Abstract
Glioblastoma multiforme (GBM) is known as the most aggressive and prevalent brain tumor with a high mortality rate. It is reported in people who are as young as 10 years old to as old as over 70 years old, exhibiting inter and intra tumor heterogeneity. There are several genomic and proteomic investigations that have been performed to find the unexplored potential targets of the drug against GBM. Therefore, certain effective targets have been taken to further validate the studies embarking on the robustness in the field of medicinal chemistry followed by testing in clinical trials. Also, The Cancer Genome Atlas (TCGA) project has identified certain overexpressed targets involved in the pathogenesis of GBM in three major pathways, i.e., tumor protein 53 (p53), retinoblastoma (RB), and receptor tyrosine kinase (RTK)/rat sarcoma virus (Ras)/phosphoinositide 3-kinase (PI3K) pathways. This review focuses on the compilation of recent developments in the fight against GBM thus, directing future research into the elucidation of pathogenesis and potential cure for GBM. Also, it highlights the potential biomarkers that have undergone extensive research and have promising prognostic and predictive values. Additionally, this manuscript analyses the advent of gene therapy and immunotherapy, unlocking the way to consider treatment approaches other than, or in addition to, conventional chemo-radiation therapies. This review study encompasses all the relevant research studies associated with the pathophysiology, occurrence, diagnostic tools, and therapeutic intervention for GBM. It highlights the evolution of various therapeutic perspectives against GBM from the most conventional form of radiotherapy to the recent advancement of gene/cell/immune therapy. Further, the review focuses on various targeted therapies for GBM including chemotherapy sensitization, radiotherapy, nanoparticles based, immunotherapy, cell therapy, and gene therapy which would offer a comprehensive account for exploring several facets related to GBM prognostics.
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Affiliation(s)
- Manisha Singh
- Department of Biotechnology, Jaypee Institute of Information Technology (JIIT), Noida 201301, India,Correspondence: Manisha Singh, Department of Biotechnology, Jaypee Institute of Information Technology (JIIT), Noida 201301, India.
| | - Divya Jindal
- Department of Biotechnology, Jaypee Institute of Information Technology (JIIT), Noida 201301, India
| | - Vinayak Agarwal
- Department of Biotechnology, Jaypee Institute of Information Technology (JIIT), Noida 201301, India
| | - Deepanshi Pathak
- Department of Biotechnology, Jaypee Institute of Information Technology (JIIT), Noida 201301, India
| | - Mansi Sharma
- Department of Biotechnology, Jaypee Institute of Information Technology (JIIT), Noida 201301, India
| | - Pranav Pancham
- Department of Biotechnology, Jaypee Institute of Information Technology (JIIT), Noida 201301, India
| | - Shalini Mani
- Department of Biotechnology, Jaypee Institute of Information Technology (JIIT), Noida 201301, India
| | - Rachana
- Department of Biotechnology, Jaypee Institute of Information Technology (JIIT), Noida 201301, India
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Subbaraj GK, Kumar YS, Kulanthaivel L. Antiangiogenic role of natural flavonoids and their molecular mechanism: an update. THE EGYPTIAN JOURNAL OF INTERNAL MEDICINE 2021. [DOI: 10.1186/s43162-021-00056-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Abstract
Background
Angiogenesis is the development of new blood vessels from the existing vasculature, which is important in normal developmental processes. Angiogenesis is a key step in tumor growth, invasion, and metastasis. Angiogenesis is necessary for the proper nourishment and removal of metabolic wastes from tumor sites. Therefore, modulation of angiogenesis is considered a therapeutic strategy of great importance for human health.
Main body
Numerous bioactive plant compounds are recently tested for their antiangiogenic potential. Among the most frequently studied are flavonoids which are abundantly present in fruits and vegetables. Flavonoids inhibit angiogenesis and metastasis through the regulation of multiple signaling pathways. Flavonoids regulate the expression of VEGF, matrix metalloproteinases (MMPs), EGFR, and inhibit NFB, PI3-K/Akt, and ERK1/2 signaling pathways, thereby causing strong antiangiogenic effects. This present review aimed to provide up-to-date information on the molecular mechanisms of antiangiogenic properties of natural flavonoids.
Conclusion
Presently developed antiangiogenic drugs in malignant growth treatment do not meet assumptions about adequacy and safety. So further investigations are needed in this field in the future. More recently, flavonoids are the most effective antiangiogenic agent, by inhibition of signaling pathways.
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Esteghlal S, Mokhtari MJ, Beyzaei Z. Quercetin Can Inhibit Angiogenesis via the Down Regulation of MALAT1 and MIAT LncRNAs in Human Umbilical Vein Endothelial Cells. Int J Prev Med 2021; 12:59. [PMID: 34447501 PMCID: PMC8356977 DOI: 10.4103/ijpvm.ijpvm_103_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 07/30/2020] [Indexed: 12/14/2022] Open
Abstract
Background: Angiogenesis is an important step in cancer metastasis since it enables the growing tumor to receive nutrients and oxygen. Quercetin is a generic flavonoid and has been investigated for its ability to inhibit angiogenesis in different types of cancers. MALAT1 and MIAT lncRNAs are associated with the angiogenesis process. MALAT1 induces hypoxia-driven angiogenesis via the overexpression of angiogenic genes. Down regulation of MIAT1 could inhibit the proliferation of endothelial cells, tube formation, and migration. In this study, we assessed the anti-angiogenic activity of quercetin on human umbilical vein endothelial cells (HUVEC) via the expression of MALAT1 and MIAT genes. Methods: In the present study, HUVEC cells were incubated with various concentrations of quercetin for 24, 48, and 72 h. Cell proliferation was then evaluated by MTT assay. RNA was extracted by TRIzol and cDNA synthesis. The expression levels of MALAT1 and MIAT genes relative to the GAPDH gene were quantified using the highly sensitive real-time PCR method. Results: Our results demonstrated that quercetin has an inhibitory impact on the cell viability of HUVEC cells. The IC50 values of quercetin after 24, 48, and 72 h were 282.05 μM, 228.25 μM, and 131.65 μM, respectively. The MALAT1/GAPDH ratio was computed as 0.21 for 24h, 0.18 for 48h, and 0.29 for 72 h. The MIAT/GAPDH ratio was computed as 0.82 for 24h, 0.84 for 48h, and 0.78 for 72 h. Conclusions: In conclusion, quercetin treatment had an anti-angiogenic effect on HUVEC cells, at least partially via the down regulation of MALAT1 and MIAT LncRNAs gene expression.
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Affiliation(s)
- Somayeh Esteghlal
- Department of Biology, Zarghan Branch, Islamic Azad University, Zarghan, Iran
| | | | - Zahra Beyzaei
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Liu N, Shan F, Ma M. Strategic enhancement of immune checkpoint inhibition in refractory Colorectal Cancer: Trends and future prospective. Int Immunopharmacol 2021; 99:108017. [PMID: 34352568 DOI: 10.1016/j.intimp.2021.108017] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 07/17/2021] [Accepted: 07/21/2021] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC), known as a frequently fatal disease, ranking as the third most common malignancy, is the second leading cause of cancer related mortality worldwide. Metastases are common in CRC patients which account for approximately 25% of the patients at diagnosis, 50% of patients during treatment which is associated closely with CRC mortality. Conventional therapies such as surgery, chemotherapy, and radiotherapy are standards of care for the treatment of CRC patients. However, primary tumor recurrence and secondary disease in patients receiving standard of care treatment modalities occur in 50% of patients so that new treatment modalities are needed. Immune checkpoint inhibition (ICI) has transformed the management of patients suffered from metastatic CRC (mCRC) with mismatch repair deficiency (dMMR) and microsatellite instability (MSI) -high (MSI-H) while manifests ineffectiveness in preserved mismatch repair (pMMR) or microsatellite stable (MSS) "cold" tumors which makes up the majority (95%) of mCRC. In this review, we mainly lay emphasis on the development of combinations in therapy strategies with ICIs with other immune based treatment approaches to increase the intra-tumoral immune response and render tumors 'immune-reactive', thereby increasing the efficacy of tumor immunotherapy.
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Affiliation(s)
- Ning Liu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning Province, China
| | - Fengping Shan
- Department of Immunology, College of Basic Medical Science, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning Province, China
| | - Mingxing Ma
- Department of Colorectal Cancer Surgery, Department of General Surgery, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning Province, China.
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Küçükler S, Çomaklı S, Özdemir S, Çağlayan C, Kandemir FM. Hesperidin protects against the chlorpyrifos-induced chronic hepato-renal toxicity in rats associated with oxidative stress, inflammation, apoptosis, autophagy, and up-regulation of PARP-1/VEGF. ENVIRONMENTAL TOXICOLOGY 2021; 36:1600-1617. [PMID: 33908150 DOI: 10.1002/tox.23156] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 04/17/2021] [Indexed: 06/12/2023]
Abstract
In this study, we investigated the effects of hesperidin (HSP) on oxidants/antioxidants status, inflammation, apoptotic, and autophagic activity in hepato-renal toxicity induced by chronic chlorpyrifos (CPF) exposure in rats. We used a total of 35 male albino rats in five groups of seven: control, HSP 100, CPF, CPF + HSP50, and CPF + HSP100. After rats were sacrificed, blood, liver, and kidney samples were collected. Serum levels of aspartate aminotransferases (ALT and AST), alkaline phosphatase (ALP), creatinine, and urea were tested. Then, contents of the superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), glutathione peroxidase (GPx), and glutathione (GSH) were measured to detect the level of oxidative stress in rat liver and renal tissues. We measured inflammatory and autophagy markers of chlorpyrifos induced oxidative stress in the liver and kidney tissues including TNF-α, iNOS, IL-1 β, COX-2, NF-κB, MAPK14, and Beclin-1 using ELISA. Histopathological findings were also examined followed by immunohistochemical determination of 8-OHdG expression. Real-time PCR (RT-PCR) was used to examine Cas-3, Bax, Bcl-2, PARP-1, and VEGF, which are associated with apoptosis, autophagy, DNA, and endothelial damage, respectively. In addition, PARP-1 activity was supported by western blot and immunofluorescence, VEGF activity was supported by western blot methods. Treatment with HSP reduced the effect of CPF on ALT, AST, ALP, and total proteins, and increased its effect on tissue antioxidants. PARP/VEGF, apoptotic, pro-apoptotic, anti-apoptotic, and autophagic gene expressions were regulated, and Caspase-3 and Bax expressions were decreased; Bcl-2 expression increased in both the liver and kidney samples, and positivity of 8-OHdG and PARP-1 were reduced in the CPF plus HSP-treated group. Overall, the study demonstrates that HSP may reduce the effects of hepato-renal toxicity caused by CPF by regulating oxidative stress, inflammation, apoptosis, autophagy, and PARP/VEGF genes at biochemical, cellular, and molecular levels.
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Affiliation(s)
- Sefa Küçükler
- Department of Biochemistry, Faculty of Veterinary Medicine, Atatürk University, Erzurum, Turkey
| | - Selim Çomaklı
- Department of Pathology, Faculty of Veterinary Medicine, Atatürk University, Erzurum, Turkey
| | - Selçuk Özdemir
- Department of Genetics, Faculty of Veterinary Medicine, Atatürk University, Erzurum, Turkey
| | - Cüneyt Çağlayan
- Department of Biochemistry, Faculty of Veterinary Medicine, Bingöl University, Bingöl, Turkey
| | - Fatih Mehmet Kandemir
- Department of Biochemistry, Faculty of Veterinary Medicine, Atatürk University, Erzurum, Turkey
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Cetinkaya A, Topal BD, Atici EB, Ozkan SA. Simple and highly sensitive assay of axitinib in dosage form and biological samples and its electrochemical behavior on the boron-doped diamond and glassy carbon electrodes. Electrochim Acta 2021. [DOI: 10.1016/j.electacta.2021.138443] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Wang L, Zhang S, Cai H, Qi Q, Zhang C, Qi Z, Huang C. Inhibition of TLR9 signaling stimulates apoptosis and cell cycle arrest and alleviates angiogenic property in human cervical cancer cells. Endocr Metab Immune Disord Drug Targets 2021; 22:510-517. [PMID: 34161216 DOI: 10.2174/1871530321666210622112753] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 04/15/2021] [Accepted: 04/20/2021] [Indexed: 12/24/2022]
Abstract
AIMS The aim of the study was to assess the effect of blocking TLR9 signaling on the proliferation of cervical cancer cells and its angiogenic property. BACKGROUND Toll-like receptors (TLRs) have been implicated for their crucial role in not only cervical cancer but also in other malignancies. TLR9 is expressed on an array of cells such as macrophages, dendritic cells, melanocytes, and keratinocytes. It is reported to modulate oncogenesis along with tumorigenesis by augmenting NF-κB mediated inflammation within the tumor environment. TLR9 has also been reported to positively regulate oncogenesis within the cervix and as a marker to evaluate malignant remodeling of cervical squamous cells. Therefore, this study was designed to explore the functional relevance of blocking the TLR9 signaling pathway in cervical cancer cells. OBJECTIVE The objective of the current study was to investigate the effect of human TLR9 antagonist, ODN INH-18, on apoptosis and cell cycle regulation and angiogenic property of human cervical cancer Caski cells. METHOD MTT assay was performed to measure cell viability, and flow cytometry analysis was performed to assess cell cycle arrest. Quantitative real-time PCR (qRT-PCR) analysis was performed to measure fold change in the gene expression of various markers of apoptosis, cell cycle regulation, and angiogenesis. RESULT The qRT-PCR results showed a higher expression level of TLR9 mRNA in Caski cervical cancer cells as compared to normal cervical keratinocytes. The apoptotic, angiogenic, and cell cycle regulatory factors were also deregulated in Caski cells in comparison to normal keratinocytes. The MTT assay demonstrated that treatment of TLR9 antagonist, ODN INH18, significantly reduced the proliferation of Caski cells in a dose-dependent manner. Treatment of ODN INH18 led to substantial cell cycle arrest in Caski cells at G0/G1 phase. Moreover, the qRT-PCR results demonstrated that ODN INH18 treatment led to suppressed mRNA expression of Bcl-2 and enhanced expression of Bax, signifying induction of apoptosis in Caski cells. Moreover, the expression of cyclin D1, Cdk4, and Cdc25A was found to be reduced, whereas expression of p27 was increased in ODN INH18-treated Caski cells, indicating G0/G1 phase arrest. Interestingly, expression of VEGF and VCAM-1 were found to be significantly inhibited in ODN INH18-treated Caski cells, substantiating alleviation of angiogenic property of cervical cancer cells. CONCLUSION The results of our study suggest that inhibiting TLR9 signaling might be an interesting therapeutic intervention for the treatment of cervical cancer.
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Affiliation(s)
- Liehong Wang
- Department of Gynecology and Obstetrics，Qinghai Red Cross Hospital，810000, China
| | - Shengkun Zhang
- Department of Gynecology and Obstetrics, Xuzhou Central Hospital; 221009, China
| | - Hua Cai
- Department of Gynecology, Maternal and Child Health Hospital of Liaocheng,252000, China
| | - Qingling Qi
- Department of Gynecology and Obstetrics，Qinghai Red Cross Hospital，810000, China
| | - Chunhua Zhang
- Department of Gynecology, Maternal and Child Health Hospital of Huai'an City, Jiangsu Province, Huai'an City, Jiangsu Province, 223002, China
| | - Ziyi Qi
- Huaiyin Middle School of Jiangsu Province, Huai'an City, Jiangsu Province, 223000, China
| | - CuiPing Huang
- Department of Obstetrics and Gynecology, The Second Hospital of Shandong University, 250033, China
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Hwang J, Yang HW, Lu YA, Je JG, Lee HG, Fernando KHN, Jeon YJ, Ryu B. Phloroglucinol and dieckol isolated from Ecklonia cava suppress impaired diabetic angiogenesis; A study of in-vitro and in-vivo. Biomed Pharmacother 2021; 138:111431. [PMID: 33752058 DOI: 10.1016/j.biopha.2021.111431] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 02/17/2021] [Accepted: 02/21/2021] [Indexed: 01/21/2023] Open
Abstract
Abnormalities in angiogenesis that are associated with diabetes may contribute to vascular complications and result in disabilities and death. Furthermore, an imbalance in angiogenesis in different tissues, including the retina and kidney, can play a role in the pathogenesis of diabetic microvascular complications. Phlorotannins, such as phloroglucinol (PG) and dieckol (DK), which are found in Ecklonia cava exhibit antioxidant and anti-inflammatory activities that improve endothelial function in hypertension. However, reports on the effects of these compounds on diabetes-induced angiogenesis in vivo and in vitro are scarce. In this study, we assessed the antiangiogenic effects of PG and DK on endothelial cells treated with a high concentration of glucose to mimic angiogenesis. In addition, we sought to determine the effects of these compounds on cell proliferation, cell migration, and capillary formation. In silico docking of PG and DK into VEGFR-2 revealed their potential as therapeutic agents against angiogenesis. Further, both compounds were identified to inhibit the formation of the retinal vessel in transgenic zebrafish (flk:EGFP) embryos under high glucose conditions. These findings suggested that PG and DK derived from E. cava are potential inhibitors of angiogenesis in diabetic vascular complications and could, therefore, be used to develop angiogenic agents.
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Affiliation(s)
- Jin Hwang
- Department of Marine Life Science, Jeju National University, Jeju 63243, South Korea
| | - Hye-Won Yang
- Department of Marine Life Science, Jeju National University, Jeju 63243, South Korea
| | - Yu An Lu
- Department of Marine Life Science, Jeju National University, Jeju 63243, South Korea
| | - Jun-Geon Je
- Department of Marine Life Science, Jeju National University, Jeju 63243, South Korea
| | - Hyo-Geun Lee
- Department of Marine Life Science, Jeju National University, Jeju 63243, South Korea
| | - K H N Fernando
- Department of Marine Life Science, Jeju National University, Jeju 63243, South Korea
| | - You-Jin Jeon
- Department of Marine Life Science, Jeju National University, Jeju 63243, South Korea; Marine Science Institute, Jeju National University, Jeju 63333, South Korea.
| | - BoMi Ryu
- Department of Marine Life Science, Jeju National University, Jeju 63243, South Korea.
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Florea A, Mottaghy FM, Bauwens M. Molecular Imaging of Angiogenesis in Oncology: Current Preclinical and Clinical Status. Int J Mol Sci 2021; 22:5544. [PMID: 34073992 PMCID: PMC8197399 DOI: 10.3390/ijms22115544] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 05/17/2021] [Accepted: 05/20/2021] [Indexed: 12/11/2022] Open
Abstract
Angiogenesis is an active process, regulating new vessel growth, and is crucial for the survival and growth of tumours next to other complex factors in the tumour microenvironment. We present possible molecular imaging approaches for tumour vascularisation and vitality, focusing on radiopharmaceuticals (tracers). Molecular imaging in general has become an integrated part of cancer therapy, by bringing relevant insights on tumour angiogenic status. After a structured PubMed search, the resulting publication list was screened for oncology related publications in animals and humans, disregarding any cardiovascular findings. The tracers identified can be subdivided into direct targeting of angiogenesis (i.e., vascular endothelial growth factor, laminin, and fibronectin) and indirect targeting (i.e., glucose metabolism, hypoxia, and matrix metallo-proteases, PSMA). Presenting pre-clinical and clinical data of most tracers proposed in the literature, the indirect targeting agents are not 1:1 correlated with angiogenesis factors but do have a strong prognostic power in a clinical setting, while direct targeting agents show most potential and specificity for assessing tumour vascularisation and vitality. Within the direct agents, the combination of multiple targeting tracers into one agent (multimers) seems most promising. This review demonstrates the present clinical applicability of indirect agents, but also the need for more extensive research in the field of direct targeting of angiogenesis in oncology. Although there is currently no direct tracer that can be singled out, the RGD tracer family seems to show the highest potential therefore we expect one of them to enter the clinical routine.
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Affiliation(s)
- Alexandru Florea
- Department of Nuclear Medicine, University Hospital RWTH Aachen, 52074 Aachen, Germany; (A.F.); (M.B.)
- Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, 6229HX Maastricht, The Netherlands
- School for Cardiovascular Diseases (CARIM), Maastricht University, 6229HX Maastricht, The Netherlands
| | - Felix M. Mottaghy
- Department of Nuclear Medicine, University Hospital RWTH Aachen, 52074 Aachen, Germany; (A.F.); (M.B.)
- Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, 6229HX Maastricht, The Netherlands
- School for Cardiovascular Diseases (CARIM), Maastricht University, 6229HX Maastricht, The Netherlands
- School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, 6229HX Maastricht, The Netherlands
| | - Matthias Bauwens
- Department of Nuclear Medicine, University Hospital RWTH Aachen, 52074 Aachen, Germany; (A.F.); (M.B.)
- Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, 6229HX Maastricht, The Netherlands
- School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, 6229HX Maastricht, The Netherlands
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Oshiro H, Tome Y, Miyake K, Higuchi T, Sugisawa N, Kanaya F, Nishida K, Hoffman RM. An mTOR and VEGFR inhibitor combination arrests a doxorubicin resistant lung metastatic osteosarcoma in a PDOX mouse model. Sci Rep 2021; 11:8583. [PMID: 33883561 PMCID: PMC8060249 DOI: 10.1038/s41598-021-87553-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 03/22/2021] [Indexed: 12/11/2022] Open
Abstract
In order to identify more effective therapy for recalcitrant osteosarcoma, we evaluated the efficacy of an mTOR-VEGFR inhibitor combination on tumor growth in a unique osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model derived from the lung metastasis of an osteosarcoma patient who failed doxorubicin therapy. We also determined the efficacy of this inhibitor combination on angiogenesis using an in vivo Gelfoam fluorescence angiogenesis mouse model implanted with osteosarcoma patient-derived cells (OS-PDCs). PDOX models were randomly divided into five groups of seven nude mice. Group 1, control; Group 2, doxorubicin (DOX); Group 3, everolimus (EVE, an mTOR and VEGF inhibitor); Group 4, pazopanib (PAZ, a VEGFR inhibitor); Group 5, EVE-PAZ combination. Tumor volume and body weight were monitored 2 times a week. The in vivo Gelfoam fluorescence angiogenesis assay was performed with implanted OS-PDCs. The nude mice with implanted Gelfoam and OSPDCs also were divided into the four therapeutic groups and vessel length was monitored once a week. The EVE-PAZ combination suppressed tumor growth in the osteosarcoma PDOX model and decreased the vessel length ratio in the in vivo Gelfoam fluorescent angiogenesis model, compared with all other groups (p < 0.05). There was no significant body-weight loss in any group. Only the EVE-PAZ combination caused tumor necrosis. The present study demonstrates that a combination of an mTOR-VEGF inhibitor and a VEGFR inhibitor was effective for a DOX-resistant lung-metastatic osteosarcoma PDOX mouse model, at least in part due to strong anti-angiogenesis efficacy of the combination.
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Affiliation(s)
- Hiromichi Oshiro
- AntiCancer Inc., 7917 Ostrow Street, San Diego, CA, 92122, USA.,Department of Surgery, University of California, San Diego, CA, USA.,Department of Orthopedic Surgery, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara-cho, Nakagami-gun, Okinawa, 903-0215, Japan
| | - Yasunori Tome
- Department of Orthopedic Surgery, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara-cho, Nakagami-gun, Okinawa, 903-0215, Japan.
| | - Kentaro Miyake
- AntiCancer Inc., 7917 Ostrow Street, San Diego, CA, 92122, USA.,Department of Surgery, University of California, San Diego, CA, USA
| | - Takashi Higuchi
- AntiCancer Inc., 7917 Ostrow Street, San Diego, CA, 92122, USA.,Department of Surgery, University of California, San Diego, CA, USA
| | - Norihiko Sugisawa
- AntiCancer Inc., 7917 Ostrow Street, San Diego, CA, 92122, USA.,Department of Surgery, University of California, San Diego, CA, USA
| | - Fuminori Kanaya
- Department of Orthopedic Surgery, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara-cho, Nakagami-gun, Okinawa, 903-0215, Japan
| | - Kotaro Nishida
- Department of Orthopedic Surgery, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara-cho, Nakagami-gun, Okinawa, 903-0215, Japan
| | - Robert M Hoffman
- AntiCancer Inc., 7917 Ostrow Street, San Diego, CA, 92122, USA. .,Department of Surgery, University of California, San Diego, CA, USA.
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Fletcher EL, Phipps JA, Wilkinson-Berka JL. Dysfunction of retinal neurons and glia during diabetes. Clin Exp Optom 2021; 88:132-45. [PMID: 15926876 DOI: 10.1111/j.1444-0938.2005.tb06686.x] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2004] [Revised: 04/15/2005] [Accepted: 04/23/2005] [Indexed: 12/27/2022] Open
Abstract
Diabetic retinopathy is the leading cause of blindness in those of working age. It is well known that the retinal vasculature is altered during diabetes. More recently, it has emerged that neuronal and glial dysfunction occurs in those with diabetes. Current research is directed at understanding these neuronal and glial changes because they may be an early manifestation of disease processes that ultimately lead to vascular abnormality. This review will highlight the recent advances in our understanding of the neuronal and glial changes that occur during diabetes.
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Affiliation(s)
- Erica L Fletcher
- Department of Anatomy and Cell Biology, The University of Melbourne, Grattan Street, Parkville, VIC 3010, Australia
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Guo L, Zou X, Gu Y, Yi L, Zhao J, Wu G. Apatinib Combined with Irinotecan in the Treatment of Advanced Small-Cell Esophageal Carcinoma: A Case Report. Onco Targets Ther 2021; 14:1989-1995. [PMID: 33776448 PMCID: PMC7987322 DOI: 10.2147/ott.s295067] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 02/16/2021] [Indexed: 12/12/2022] Open
Abstract
Chemotherapy is the mainstay of treatment for advanced small cell esophageal carcinoma (SCEC) characterized by poor prognosis. Preclinical studies demonstrated that apatinib has the potential to enhance the efficacy of conventional chemotherapeutic drugs and reverse multidrug resistance (MDR). This report described the application of apatinib combined with irinotecan as the third-line treatment for advanced SCEC in a 54-year-old male patient. His symptoms of upper abdominal pain and distension were ameliorated notably after the combination therapy. Computed tomography (CT) examination revealed the treatment efficacy was partial response (PR). The progression-free survival (PFS) and overall survival (OS) were 12.5 months and 28 months, respectively. The treatment-related toxicity was manageable. Apatinib combined with chemotherapy may serve as a new treatment choice for advanced SCEC patients. However, further studies should be conducted to confirm the therapeutic value of this combination regimen in advanced SCEC.
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Affiliation(s)
- Longhua Guo
- Department of Medical Oncology, Cancer Center, Meizhou People's Hospital (Huangtang Hospital), Meizhou Hospital Affiliated to Sun Yat-Sen University, Meizhou, 514031, People's Republic of China
| | - Xiaofang Zou
- Department of Medical Oncology, Cancer Center, Meizhou People's Hospital (Huangtang Hospital), Meizhou Hospital Affiliated to Sun Yat-Sen University, Meizhou, 514031, People's Republic of China
| | - Yinfang Gu
- Department of Medical Oncology, Cancer Center, Meizhou People's Hospital (Huangtang Hospital), Meizhou Hospital Affiliated to Sun Yat-Sen University, Meizhou, 514031, People's Republic of China
| | - Lilan Yi
- Department of Medical Oncology, Cancer Center, Meizhou People's Hospital (Huangtang Hospital), Meizhou Hospital Affiliated to Sun Yat-Sen University, Meizhou, 514031, People's Republic of China
| | - Jingjing Zhao
- Department of Biotherapy, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, People's Republic of China
| | - Guowu Wu
- Department of Medical Oncology, Cancer Center, Meizhou People's Hospital (Huangtang Hospital), Meizhou Hospital Affiliated to Sun Yat-Sen University, Meizhou, 514031, People's Republic of China
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Silverman DA, Martinez VK, Dougherty PM, Myers JN, Calin GA, Amit M. Cancer-Associated Neurogenesis and Nerve-Cancer Cross-talk. Cancer Res 2021; 81:1431-1440. [PMID: 33334813 PMCID: PMC7969424 DOI: 10.1158/0008-5472.can-20-2793] [Citation(s) in RCA: 130] [Impact Index Per Article: 32.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 11/17/2020] [Accepted: 12/11/2020] [Indexed: 11/16/2022]
Abstract
In this review, we highlight recent discoveries regarding mechanisms contributing to nerve-cancer cross-talk and the effects of nerve-cancer cross-talk on tumor progression and dissemination. High intratumoral nerve density correlates with poor prognosis and high recurrence across multiple solid tumor types. Recent research has shown that cancer cells express neurotrophic markers such as nerve growth factor, brain-derived neurotrophic factor, and glial cell-derived neurotrophic factor and release axon-guidance molecules such as ephrin B1 to promote axonogenesis. Tumor cells recruit new neural progenitors to the tumor milieu and facilitate their maturation into adrenergic infiltrating nerves. Tumors also rewire established nerves to adrenergic phenotypes via exosome-induced neural reprogramming by p53-deficient tumors. In turn, infiltrating sympathetic nerves facilitate cancer progression. Intratumoral adrenergic nerves release noradrenaline to stimulate angiogenesis via VEGF signaling and enhance the rate of tumor growth. Intratumoral parasympathetic nerves may have a dichotomous role in cancer progression and may induce Wnt-β-catenin signals that expand cancer stem cells. Importantly, infiltrating nerves not only influence the tumor cells themselves but also impact other cells of the tumor stroma. This leads to enhanced sympathetic signaling and glucocorticoid production, which influences neutrophil and macrophage differentiation, lymphocyte phenotype, and potentially lymphocyte function. Although much remains unexplored within this field, fundamental discoveries underscore the importance of nerve-cancer cross-talk to tumor progression and may provide the foundation for developing effective targets for the inhibition of tumor-induced neurogenesis and tumor progression.
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Affiliation(s)
- Deborah A Silverman
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Vena K Martinez
- Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Patrick M Dougherty
- Department of Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jeffrey N Myers
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - George A Calin
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Moran Amit
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Nada H, Elkamhawy A, Lee K. Structure Activity Relationship of Key Heterocyclic Anti-Angiogenic Leads of Promising Potential in the Fight against Cancer. Molecules 2021; 26:molecules26030553. [PMID: 33494492 PMCID: PMC7865909 DOI: 10.3390/molecules26030553] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 01/13/2021] [Accepted: 01/18/2021] [Indexed: 12/11/2022] Open
Abstract
Pathological angiogenesis is a hallmark of cancer; accordingly, a number of anticancer FDA-approved drugs act by inhibiting angiogenesis via different mechanisms. However, the development process of the most potent anti-angiogenics has met various hurdles including redundancy, multiplicity, and development of compensatory mechanisms by which blood vessels are remodeled. Moreover, identification of broad-spectrum anti-angiogenesis targets is proved to be required to enhance the efficacy of the anti-angiogenesis drugs. In this perspective, a proper understanding of the structure activity relationship (SAR) of the recent anti-angiogenics is required. Various anti-angiogenic classes have been developed over the years; among them, the heterocyclic organic compounds come to the fore as the most promising, with several drugs approved by the FDA. In this review, we discuss the structure–activity relationship of some promising potent heterocyclic anti-angiogenic leads. For each lead, a molecular modelling was also carried out in order to correlate its SAR and specificity to the active site. Furthermore, an in silico pharmacokinetics study for some representative leads was presented. Summarizing, new insights for further improvement for each lead have been reviewed.
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Affiliation(s)
- Hossam Nada
- College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Korea
| | - Ahmed Elkamhawy
- College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Korea
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Kyeong Lee
- College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Korea
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Kariper IA, Üstündağ Z, Caglayan MO. A sensitive spectrophotometric ellipsometry based Aptasensor for the vascular endothelial growth factor detection. Talanta 2020; 225:121982. [PMID: 33592730 DOI: 10.1016/j.talanta.2020.121982] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 12/02/2020] [Accepted: 12/05/2020] [Indexed: 01/02/2023]
Abstract
A sensitive and selective, aptamer and spectroscopic ellipsometry based sensor is reported here for the early diagnosis of breast cancer, which is a common type of cancer following lung cancer. It was aimed to develop a single-step and label-free assay for the sensitive and selective detection of VEGF165. To this end, two different aptamers and spectroscopic ellipsometry were used. In the presented study, by determining the appropriate aptamer immobilization conditions, the spectroscopic ellipsometry technique was successfully applied for the detection of VEGF165 at the range of 1 pM-1000 pM in the buffer. Aptasensors have a detection limit of 5.81 pM and 4.29 pM, respectively.
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Affiliation(s)
| | - Zafer Üstündağ
- Dumlupinar University, Chemistry Department, 43100, Kütahya, Turkey
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41
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Okamoto M, Watanabe M, Inoue N, Ogawa K, Hidaka Y, Iwatani Y. Gene polymorphisms of VEGF and VEGFR2 are associated with the severity of Hashimoto's disease and the intractability of Graves' disease, respectively. Endocr J 2020; 67:545-559. [PMID: 32074519 DOI: 10.1507/endocrj.ej19-0480] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Vascular endothelial growth factor (VEGF) is one of main regulators of angiogenesis that functions by binding to its receptors, including VEGF receptor (VEGFR) 2. There are few data available regarding the association between VEGF and VEGFR polymorphisms and the susceptibility to and prognosis of autoimmune thyroid diseases (AITDs). To elucidate this association, we genotyped four functional VEGF and two VEGFR2 polymorphisms and measured serum VEGF levels. In the four functional VEGF polymorphisms, the frequencies of the I carrier and I allele of VEGF -2549 I/D, which has lower activity, were higher in patients with severe HD than in those with mild HD. In the two functional VEGFR2 polymorphisms, the frequency of the rs2071559 CC genotype, which has higher activity, was higher in patients with intractable GD than in controls, and the proportion of GD patients with larger goiters was higher in those with the CC genotype. Moreover, the frequency of the rs1870377 TT genotype with higher activity was higher in patients with intractable GD than in those with GD in remission. Combinations of VEGF and VEGFR2 polymorphisms with stronger interactions were associated with the intractability of GD. Serum VEGF levels were higher in HD and AITD patients than those in controls. In conclusion, VEGF polymorphisms with lower activity were associated with the severity of HD, while VEGFR2 polymorphisms and the combinations of VEGF and VEGFR2 polymorphisms, which have stronger interactions, were associated with the intractability of GD. VEGF and VEGFR2 polymorphisms were associated with HD severity and GD intractability, respectively.
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Affiliation(s)
- Mami Okamoto
- Department of Biomedical Informatics, Division of Health Sciences, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Mikio Watanabe
- Department of Biomedical Informatics, Division of Health Sciences, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Naoya Inoue
- Department of Biomedical Informatics, Division of Health Sciences, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
- Laboratory for Clinical Investigation, Osaka University Hospital, Osaka 565-0871, Japan
| | - Kazane Ogawa
- Department of Biomedical Informatics, Division of Health Sciences, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Yoh Hidaka
- Laboratory for Clinical Investigation, Osaka University Hospital, Osaka 565-0871, Japan
| | - Yoshinori Iwatani
- Department of Biomedical Informatics, Division of Health Sciences, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
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Dai X, Fu Y, Ye Y. Increased NDRG1 expression suppresses angiogenesis via PI3K/AKT pathway in human placental cells. Pregnancy Hypertens 2020; 21:106-110. [PMID: 32470876 DOI: 10.1016/j.preghy.2020.05.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 04/26/2020] [Accepted: 05/20/2020] [Indexed: 01/07/2023]
Abstract
OBJECTIVE To observe whether and how N-myc downstream-regulated gene 1 (NDRG1) regulates placental angiogenesis via JEG-3 placental-derived cells. METHODS Expression of NDRG1 in stably transfected JEG-3 cells was detected using western blot and real-time quantitative polymerase chain reaction. Angiogenesis was examined by tube formation assay. The levels of placental growth factor (PLGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were examined using enzyme-linked immunosorbent assay. The expression of vascular endothelial growth factor (VEGF), PI3K, and AKT was examined by western blot. The relationship between PI3K and NDRG1 was detected by co-immunoprecipitation. RESULTS NDRG1 was significantly down-regulated at both the mRNA and protein level by lentivirus (Lv)-NDRG1-shRNA (P < 0.001), whereas it was significantly up-regulated by Lv-NDRG1 (P < 0.001). NDRG1 knockdown significantly increase the expression of PLGF and VEGF in JEG-3 cells (P < 0.001), while NDRG1 knockdown significantly reduced the secretion of sFlt-1 (P < 0.001). NDRG1 was specific bound to PI3K, and NDRG1 knockdown significantly up-regulated the expressions of PI3K and AKT in JEG-3 cells (P < 0.001). CONCLUSION NDRG1 suppresses angiogenesis in preeclampsia, and the PI3K/AKT signaling pathway may be involved in the regulation of angiogenesis by NDRG1.
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Affiliation(s)
- Xueli Dai
- Department of Obstetrics and Gynecology, Qingdao University, Qingdao 266000, China; Department of Obstetrics, Zibo Maternal and Child Health Hospital, Zibo 255000, China
| | - Yufen Fu
- Department of Obstetrics, Zibo Maternal and Child Health Hospital, Zibo 255000, China
| | - Yuanhua Ye
- Department of Obstetrics and Gynecology, Qingdao University, Qingdao 266000, China; Department of Obstetrics, Affiliated Hospital of Qingdao University, Qingdao 266000, China.
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Zhu M, Molina JR, Dy GK, Croghan GA, Qi Y, Glockner J, Hanson LJ, Roos MM, Tan AD, Adjei AA. A phase I study of the VEGFR kinase inhibitor vatalanib in combination with the mTOR inhibitor, everolimus, in patients with advanced solid tumors. Invest New Drugs 2020; 38:1755-1762. [PMID: 32328844 DOI: 10.1007/s10637-020-00936-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 04/07/2020] [Indexed: 11/26/2022]
Abstract
Purpose Combining small-molecule inhibitors of different targets was shown to be synergistic in preclinical studies. Testing this concept in clinical trials is, however, daunting due to challenges in toxicity management and efficacy assessment. This study attempted to evaluate the safety and efficacy of vatalanib plus everolimus in patients with advanced solid tumors and explore the utility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) studies as a predictive biomarker. Patients and Methods This single-center, phase I trial containing 70 evaluable patients consisted of a dose escalation proportion based on the traditional "3 + 3" design (cohort IA and IB) and a dose expansion proportion (cohort IIA and IIB). Toxicity was evaluated using the Common Terminology Criteria of Adverse Events. Antitumor activity was assessed using the Modified Response Evaluation Criteria in Solid Tumors. Results The maximum tolerated doses were determined to be vatalanib 1250 mg once daily or 750 mg twice daily in combination with everolimus 10 mg once daily. No treatment-related death occurred. The most common toxicities were hypertriglyceridemia, hypercholesterolemia, fatigue, vomiting, nausea and diarrhea. There was no complete response. Nine patients (12.9%) had partial response (PR) and 41 (58.6%) had stable disease (SD). Significant antitumor activity was observed in neuroendocrine tumors with a disease-control rate (PR + SD) of 66.7% and other tumor types including renal cancer, melanoma, and non-small-cell lung cancer. Conclusions The combination of vatalanib and everolimus demonstrated reasonable toxicity and clinical activity. Future studies combining targeted therapies and incorporating biomarker analysis are warranted based on this phase I trial.
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Affiliation(s)
- Mojun Zhu
- Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA
| | | | - Grace K Dy
- Roswell Park Cancer Institute, Buffalo, NY, 14263, USA
| | - Gary A Croghan
- Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA
| | - Yingwei Qi
- Dignity Health Medical Foundation, San Francisco, CA, 94107, USA
| | - James Glockner
- Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA
| | | | | | - Angelina D Tan
- Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA
| | - Alex A Adjei
- Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
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Nguyen VT, Canciani B, Cirillo F, Anastasia L, Peretti GM, Mangiavini L. Effect of Chemically Induced Hypoxia on Osteogenic and Angiogenic Differentiation of Bone Marrow Mesenchymal Stem Cells and Human Umbilical Vein Endothelial Cells in Direct Coculture. Cells 2020; 9:cells9030757. [PMID: 32204578 PMCID: PMC7140659 DOI: 10.3390/cells9030757] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 03/16/2020] [Accepted: 03/17/2020] [Indexed: 12/12/2022] Open
Abstract
Bone is an active tissue where bone mineralization and resorption occur simultaneously. In the case of fracture, there are numerous factors required to facilitate bone healing including precursor cells and blood vessels. To evaluate the interaction between bone marrow-derived mesenchymal stem cells (BMSC)—the precursor cells able to differentiate into bone-forming cells and human umbilical vein endothelial cells (HUVEC)—a cell source widely used for the study of blood vessels. We performed direct coculture of BMSC and HUVEC in normoxia and chemically induced hypoxia using Cobalt(II) chloride and Dimethyloxaloylglycine and in the condition where oxygen level was maintained at 1% as well. Cell proliferation was analyzed by crystal violet staining. Osteogenesis was examined by Alizarin Red and Collagen type I staining. Expression of angiogenic factor-vascular endothelial growth factor (VEGF) and endothelial marker-von Willebrand factor (VWF) were demonstrated by immunohistochemistry and enzyme-linked immunosorbent assay. The quantitative polymerase chain reaction was also used to evaluate gene expression. The results showed that coculture in normoxia could retain both osteogenic differentiation and endothelial markers while hypoxic condition limits cell proliferation and osteogenesis but favors the angiogenic function even after 1 of day treatment.
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Affiliation(s)
- Van Thi Nguyen
- IRCCS Istituto Ortopedico Galeazzi, 20161 Milan, Italy; (V.T.N.); (B.C.); (G.M.P.)
| | - Barbara Canciani
- IRCCS Istituto Ortopedico Galeazzi, 20161 Milan, Italy; (V.T.N.); (B.C.); (G.M.P.)
| | - Federica Cirillo
- Stem Cells for Tissue Engineering Laboratory, IRCCS Policlinico San Donato, 20097 San Donato Milanese, Italy; (F.C.)
| | - Luigi Anastasia
- Stem Cells for Tissue Engineering Laboratory, IRCCS Policlinico San Donato, 20097 San Donato Milanese, Italy; (F.C.)
- Università Vita-Salute San Raffaele, 20132 Milan, Italy
| | - Giuseppe M. Peretti
- IRCCS Istituto Ortopedico Galeazzi, 20161 Milan, Italy; (V.T.N.); (B.C.); (G.M.P.)
- Department of Biomedical Sciences for Health, University of Milan, 20133 Milan, Italy
| | - Laura Mangiavini
- IRCCS Istituto Ortopedico Galeazzi, 20161 Milan, Italy; (V.T.N.); (B.C.); (G.M.P.)
- Department of Biomedical Sciences for Health, University of Milan, 20133 Milan, Italy
- Correspondence: ; Tel.: +39-02-6621-4494
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Iodine Parameters in Triple-Bolus Dual-Energy CT Correlate With Perfusion CT Biomarkers of Angiogenesis in Renal Cell Carcinoma. AJR Am J Roentgenol 2020; 214:808-816. [PMID: 32069083 DOI: 10.2214/ajr.19.21969] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
OBJECTIVE. The purpose of this study is to determine the degree of the relationship between perfusion CT (PCT) parameters and iodine concentration metrics derived from triple-bolus dual-energy CT (DECT) and to compare the radiation dose delivered. SUBJECTS AND METHODS. This single-center prospective study was conducted from October 2015 to September 2017. Twenty-three consenting adults (15 men and eight women; mean [± SD] age, 56 ± 13 years [range, 25-78 years]) with renal cell carcinomas underwent consecutive PCT and triple-bolus DECT examinations. Triple-bolus DECT consisted of synchronous corticomedullary, nephrographic, and delayed phase scans acquired using a dual-source DECT scanner. Two readers independently analyzed blood flow, blood volume, and permeability, as measured by PCT, and iodine density and iodine ratio, as measured by triple-bolus DECT. Size-specific dose estimates were calculated for both groups. RESULTS. Interreader agreement was good for permeability (intraclass correlation coefficient [ICC] =.812) and blood flow (ICC = 0.849) and excellent for blood volume (ICC = 0.956), iodine density (ICC = 0.961), and iodine ratio (ICC = 0.956). Very strong positive correlations were found between blood volume and iodine density (p < 0.001) and between blood volume and iodine ratio (p < 0.001). Strong positive correlations were found between blood flow and iodine density (p < 0.001) and between blood flow and iodine ratio (p < 0.001). The correlations between permeability and iodine density (p = 0.01) and between permeability and iodine ratio (p = 0.02) were moderate. The mean size-specific dose estimate of triple-bolus DECT was approximately 15 times lower than that of PCT (p < 0.001). CONCLUSION. Quantitative iodine metrics derived from triple-bolus DECT showed significant correlation with CT parameters in renal cell carcinoma, with a significantly lower radiation dose.
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Park JH, Seo JH, Jeon HY, Seo SM, Lee HK, Park JI, Kim JY, Choi YK. Lentivirus-Mediated VEGF Knockdown Suppresses Gastric Cancer Cell Proliferation and Tumor Growth in vitro and in vivo. Onco Targets Ther 2020; 13:1331-1341. [PMID: 32104000 PMCID: PMC7025738 DOI: 10.2147/ott.s234344] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 02/02/2020] [Indexed: 01/17/2023] Open
Abstract
Purpose Gastric cancer has a high mortality rate worldwide. Although treatments, such as molecular-targeted therapy, have been introduced, the resulting long-term survival and prognosis remain unsatisfactory. Downregulation of the target genes using lentivirus-mediated short hairpin RNA (shRNA) can be an effective therapeutic strategy for patients with gastric cancer. Overexpressed vascular endothelial growth factor A (VEGF) in human gastric cancer cells can be an effective novel therapeutic target for human gastric cancer. Thus, this study aimed to evaluate the therapeutic effects of lentivirus-mediated knockdown of VEGF gene expression in human gastric cancer growth. Materials and Methods Specific shRNA sequences targeting VEGF were designed to construct a lentiviral expression vector. After human gastric carcinoma cells (cell line NCI-N87) were infected with the lentiviral vector, the therapeutic effects of the lentivirus-mediated shRNA targeting VEGF were analyzed both in vitro and in vivo. Results Stable suppression of VEGF gene expression in NCI-N87 cells using shRNA (ShVEGF) showed significant inhibition of cell proliferation, clonogenicity, and cell motility. ShVEGF also showed increased G0/G1 cell cycle arrest and apoptosis. In addition, in vivo results from nude mice xenografted ShVEGF showed significant inhibition of tumor growth. Assessing the therapeutic effects of intratumoral injection of lentivirus-targeting VEGF (Virus_VEGF) revealed that it significantly inhibited tumor growth compared to that in the Virus_Scramble or saline injection control groups. Conclusion The constructed ShVEGF showed significant inhibition of NCI-N87 gastric cancer cell growth both in vitro and in vivo. These experimental results suggest a novel therapeutic strategy for patients with gastric cancer using lentivirus-mediated shRNA targeting VEGF.
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Affiliation(s)
- Jong-Hyung Park
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk University, Seoul 05029, Republic of Korea.,Helixmith Co. Ltd., Seoul 08826, Republic of Korea
| | - Jin-Hee Seo
- Laboratory Animal Center, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea
| | - Hee-Yeon Jeon
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk University, Seoul 05029, Republic of Korea.,Department of Core Research Laboratory, Clinical Research Institute, Kyung Hee University Hospital at Gangdong, Seoul 05278, Republic of Korea
| | - Sun-Min Seo
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk University, Seoul 05029, Republic of Korea
| | - Han-Kyul Lee
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk University, Seoul 05029, Republic of Korea
| | - Jin-Il Park
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk University, Seoul 05029, Republic of Korea.,Helixmith Co. Ltd., Seoul 08826, Republic of Korea
| | - Jun-Young Kim
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk University, Seoul 05029, Republic of Korea
| | - Yang-Kyu Choi
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk University, Seoul 05029, Republic of Korea
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Rathi E, Kumar A, Suvarna, Kini G. Design of Potential Inhibitors and Prediction of their Activity by the Structural Insight of VEGFR2 Inhibitors: Atom‐based 3D‐QSAR, Fingerprint‐based 2D QSAR and Off‐target analysis. ChemistrySelect 2020. [DOI: 10.1002/slct.201903898] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Affiliation(s)
- Ekta Rathi
- Department of Pharmaceutical Chemistry Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Madhav Nagar, Manipal Karnataka India- 576104
| | - Avinash Kumar
- Department of Pharmaceutical Chemistry Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Madhav Nagar, Manipal Karnataka India- 576104
| | - Suvarna
- Department of Pharmaceutical Chemistry Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Madhav Nagar, Manipal Karnataka India- 576104
| | - G. Kini
- Department of Pharmaceutical Chemistry Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Madhav Nagar, Manipal Karnataka India- 576104
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Gao F, Yang C. Anti-VEGF/VEGFR2 Monoclonal Antibodies and their Combinations with PD-1/PD-L1 Inhibitors in Clinic. Curr Cancer Drug Targets 2020; 20:3-18. [PMID: 31729943 DOI: 10.2174/1568009619666191114110359] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 08/29/2019] [Accepted: 09/19/2019] [Indexed: 12/21/2022]
Abstract
The vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) signaling pathway is one of the most important pathways responsible for tumor angiogenesis. Currently, two monoclonal antibodies, anti-VEGF-A antibody Bevacizumab and anti-VEGFR2 antibody Ramucizumab, have been approved for the treatment of solid tumors. At the same time, VEGF/VEGFR2 signaling is involved in the regulation of immune responses. It is reported that the inhibition of this pathway has the capability to promote vascular normalization, increase the intra-tumor infiltration of lymphocytes, and decrease the number and function of inhibitory immune cell phenotypes, including Myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and M2 macrophages. On this basis, a number of clinical studies have been performed to investigate the therapeutic potential of VEGF/VEGFR2-targeting antibodies plus programmed cell death protein 1 (PD-1)/ programmed cell death ligand 1 (PD-L1) inhibitors in various solid tumor types. In this context, VEGF/VEGFR2- targeting antibodies, Bevacizumab and Ramucizumab are briefly introduced, with a description of the differences between them, and the clinical studies involved in the combination of Bevacizumab/ Ramucizumab and PD-1/PD-L1 inhibitors are summarized. We hope this review article will provide some valuable clues for further clinical studies and usages.
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Affiliation(s)
- Feng Gao
- BuChang (Beijing) Pharmaceutical Co. Ltd, Hongda Industrial Park, Hongda North Road, Beijing 100176, China
| | - Chun Yang
- BuChang (Beijing) Pharmaceutical Co. Ltd, Hongda Industrial Park, Hongda North Road, Beijing 100176, China
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Ko CN, Sun H, Wu KJ, Leung CH, Ren K, Ma DL. A portable oligonucleotide-based microfluidic device for the detection of VEGF 165 in a three-step suspended-droplet mode. Dalton Trans 2019; 48:9824-9830. [PMID: 31147654 DOI: 10.1039/c9dt00427k] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Vascular endothelial growth factor (VEGF165), an important glycosylated protein from the VEGF family, is a type of signal protein highly associated with the development and progression of cancers. In this work, we designed a G-quadruplex-based aptasensing platform for the sensitive and selective detection of VEGF165 in aqueous solution and red blood cell solution. A long-lived phosphorescence iridium(iii) complex (1) with promising photophysical properties and a large Stokes shift was chosen as a selective G-quadruplex probe. The platform could achieve a limit of detection (LOD) down to the picomolar level using a conventional fluorometer. Furthermore, we successfully applied the platform to a three-step suspended droplet (SD)-based microfluidic device for the monitoring of VEGF165. In contrast to the channel-based and digital microfluidic chips, SD-based chips allow easy introduction of liquid samples, valve-free manipulation of multiple reaction steps and flexible volume range. Importantly, polypropylene (PP), a hydrophobic and thermally stable material, was chosen as a substrate to fabricate the chip for the SD-based microfluidic device. The PP-based chip allows the combination of superhydrophobic force, gravity and surface tension for effective driving of the suspended droplet throughout the channel without reverse migration. After assembling all the major components, including a UV lamp, a rotatable chip holder, a filter and a camera into the portable device, we successfully demonstrated the applicability of the device to detect VEGF165 in aqueous solution with a LOD of 0.33 nM at a signal-to-noise ratio (S/N) of 3 and a linear range of 1-100 nM.
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Affiliation(s)
- Chung-Nga Ko
- Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.
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Xu J, Liu X, Yang S, Shi Y. Apatinib Monotherapy or Combination Therapy for Non-Small Cell Lung Cancer Patients With Brain Metastases. Oncol Res 2019; 28:127-133. [PMID: 31610827 PMCID: PMC7851530 DOI: 10.3727/096504019x15707896762251] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Apatinib, an oral small molecular receptor tyrosine kinase inhibitor (TKI) developed first in China, exerts antiangiogenic and antineoplastic function through selectively binding and inhibiting vascular endothelial growth factor receptor 2 (VEGFR-2). In this study, we aimed to explore the efficacy and safety profile of apatinib monotherapy, or combined with chemotherapy or endothelial growth factor receptor (EGFR)-TKI in heavily pretreated non-small cell lung cancer (NSCLC) patients with brain metastases. We performed a retrospective analysis for relapsed NSCLC patients with brain metastases from our institute, who received apatinib (250 mg or 500 mg p.o. qd) monotherapy, or combination with EGFR-TKI or chemotherapy as second or more line systemic therapy until disease progression or unacceptable toxicity occurred. The objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), median overall survival (mOS), and safety were analyzed. A total of 26 eligible patients were included: 24 patients diagnosed with adenocarcinoma, 2 with squamous carcinoma, and 14 patients harboring EGFR sensitizing mutations. The mPFS and mOS were 4.93 (range, 0.27–32.91; 95% CI 3.64–6.22) and 14.70 (range, 0.27–32.91; 95% CI 0.27–43.60) months for the whole group. The ORR and DCR were 7.7% (2/26) and 69.2% (18/26) for the entire lesions, and 7.7% (2/26) and 79.6% (20/26) for brain metastases, respectively. Compared with patients who received apatinib monotherapy, patients who received apatinib combination treatment had more favorable mPFS (11.77 vs. 2.27 months, p < 0.05) and mOS (24.03 vs. 6.07 months, p < 0.05). Treatment-related toxicities were tolerable including grade 1/2 hypertension, hand-and-foot syndrome, fatigue, nausea, liver dysfunction, myelosuppression, skin rash, and palpitation. In conclusion, apatinib exhibited high activity and good tolerance for NSCLC patients with brain metastasis, and it might become a potential choice for metastatic brain tumors in NSCLC patients.
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Affiliation(s)
- Jianping Xu
- Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP.R. China
| | - Xiaoyan Liu
- Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP.R. China
| | - Sheng Yang
- Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP.R. China
| | - Yuankai Shi
- Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP.R. China
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