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Jiang J, Hu R, Li Z, He W. Antibody MYH9 and Antibiotic Lidamycin Inhibit the Growth and Proliferation of Lung Cancer Cells and Induce Their Apoptosis. Mol Biotechnol 2025; 67:2732-2742. [PMID: 38997500 DOI: 10.1007/s12033-024-01235-1] [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: 12/24/2023] [Accepted: 07/01/2024] [Indexed: 07/14/2024]
Abstract
The aim of this study was to investigate the impact of the antibiotic lidamycin (LDM) and the targeted therapy with the antibody Myosin heavy chain 9 (MYH9) on cancer cells, aiming to provide insights for cancer treatment. In this study, antibiotics and targeted antibodies were used in cancer cells, and then their effects on cell growth, proliferation, apoptosis regulation, and related proteins were measured, and comparative analysis was conducted on the effects of different drug concentrations on the growth of cancer cells. In H460, the apoptotic effect of 2 nM LDM on cells reached 70%. LDM had a downward trend on the levels of B-cell lymphoma-2 (Bcl-2) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in cells. The inhibitory effects of LDM at different concentrations on human large cell lung cancer H460 transplanted tumor in nude mice reached 53.20% and 69.80%, and the inhibitory effects on the growth of lung adenocarcinoma transplanted tumor in nude mice reached 40.20% and 58.30%. The expression of MYH9 (myosin, heavy polypeptide 9, non-muscle) in human lung cancer tissues and adjacent tissues reached more than 80%. At the concentration of 300 μM, antibody MYH9 inhibited cell growth by 30%, and the migration rate was also reduced by 25%. The inhibitory effect of siRNA after knocking out the MYH9 gene on cancer cells reached 70%. Antibiotic LDM and targeted antibody MYH9 can inhibit the growth, proliferation, and migration of cancer cells, promote cancer cell apoptosis, and have certain clinical significance for the treatment of cancer patients.
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Affiliation(s)
- Jie Jiang
- Department of Cardiothoracic Surgery, Zhongda Hospital, Southeast University, Nanjing, 210009, Jiangsu Province, China
| | - Ruoyu Hu
- Department of Cardiothoracic Surgery, Zhongda Hospital, Southeast University, Nanjing, 210009, Jiangsu Province, China
| | - Zhuoshuan Li
- Department of Cardiothoracic Surgery, Zhongda Hospital, Southeast University, Nanjing, 210009, Jiangsu Province, China
| | - Wei He
- Department of Cardiothoracic Surgery, Zhongda Hospital, Southeast University, Nanjing, 210009, Jiangsu Province, China.
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Alaei E, Farahani N, Orouei S, Alimohammadi M, Daneshi S, Mousavi T, Mahmoodieh B, Taheriazam A, Rahimzadeh P, Hashemi M. The clinicopathologic and prognostic value of CD44 expression in patients with non-small cell lung cancer: A systematic review and meta-analysis. Mol Cell Probes 2025; 81:102028. [PMID: 40139282 DOI: 10.1016/j.mcp.2025.102028] [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: 11/21/2024] [Revised: 03/13/2025] [Accepted: 03/23/2025] [Indexed: 03/29/2025]
Abstract
BACKGROUND CD44 is a promising target in the prognosis and treatment of non-small cell lung cancer (NSCLC). The study deals with systematic review and meta-analysis to determine the association between CD44 overexpression and survival and clinicopathological characteristics in NSCLC patients. METHODS We used the databases Google Scholar, Web of Science, PubMed, Scopus, EMBASE, and Cochrane to conduct a systematic search of English-language literature published up to September 2023. The eligible studies were retrieved on CD44 expression, clinicopathological characteristics in NSCLC patients, and reported survival rates. The Cochran's and Higgins I2 tests were used to measure heterogeneity across the included studies. P < 0.05 was considered statistically significant in all cases. The sources of heterogeneity across the included studies were identified using subgroup analysis on histology (SCC, ADC, and LCC), tumor differentiation (well, moderate, and poor), TMN stage (I/II/III/IV), OS, and lymph node metastasis (negative and positive). All statistical analyses were carried out using meta-analysis (CMA) software. RESULTS The final analysis for prognostic significance and clinicopathological features on 3681 participants from 25 eligible studies. The pooled event rate of overexpression CD44 for overall survival in NSCLC was 38 % and was related to SCC with 76.6 %. Furthermore, subgroup analysis revealed a link between CD44 overexpression and moderate tumor differentiation (41.8 %). There was a substantial difference in CD44 overexpression in males, with 69.3 % (95 % CI: 64.3-73.9 %, I2 = 88.25 %) versus 31.5 % (95 % CI: 26.7-36.8 %, I2 = 92.15 %) in females. However, no significant relationship was observed between CD44 overexpression and TMN stages/lymph node metastasis. CONCLUSION The meta-analysis demonstrated that CD44 is an effective prognostic factor for NSCLC. Overexpression of CD44 has been linked to moderate tumor differentiation, SCC tumor histology, and a worse survival rate. However, no substantial relationship was found between CD44 and metastasis or TMN stages. Large-scale prospective research is required to validate CD44's clinical value as an unbiased prognostic indicator.
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Affiliation(s)
- Elmira Alaei
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sima Orouei
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Salman Daneshi
- Department of Public Health, School of Health, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Tahoora Mousavi
- Molecular and Cell Biology Research Center, Hemoglobinopathy Institute, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Behnaz Mahmoodieh
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Payman Rahimzadeh
- Surgical Research Society (SRS), Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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Li J, Shi X, Zhang H, Lin X, Zheng S, Chen W, Zhou Y, Liang Z. Clinical Validation of a Targeted RNA-Sequencing Assay for Driver Gene Alteration Detection in Non-Small Cell Lung Cancer. Mol Diagn Ther 2025; 29:381-391. [PMID: 40087257 DOI: 10.1007/s40291-025-00774-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/17/2025] [Indexed: 03/17/2025]
Abstract
BACKGROUND AND OBJECTIVE With the increasing number of diagnostic biomarkers associated with tumor diagnosis, targeted therapy, and immunotherapy, access to clinical pathological specimens of an appropriate size for analysis is becoming a problem. Conventional high-throughput sequencing assays for non-small cell lung cancer (NSCLC) often necessitate the extraction of separate DNA and RNA samples to achieve precise detection of various mutation types. This study aimed to employ RNA-next-generation sequencing (NGS) technology to simultaneously detect different types of mutations in NSCLC samples, including single nucleotide variations, insertions and deletions, fusions/rearrangements, and exon skipping, thereby addressing the issue of limited sample availability. METHODS Two hundred and twenty cases of formalin-fixed paraffin-embedded NSCLC clinical specimens were retrospectively included for targeted RNA sequencing based on the principle of probe hybridization capture. Lung cancer tissue samples with different storage times were compared for success in DNA-NGS and RNA-NGS assays. The clinical detection performance of RNA-NGS was evaluated by comparing its results to those of DNA-NGS and clinical assays. Samples with inconsistent results were further verified by immunohistochemistry, amplification refractory mutation system-polymerase chain reaction, or droplet digital polymerase chain reaction. RESULTS DNA-NGS exhibited an overall success rate of 91.82% in all samples, while RNA-NGS achieved an overall success rate of 92.73%. However, the success rate declined with longer storage times. Compared with DNA-NGS, targeted RNA sequencing for single nucleotide variation/insertion and deletion detection achieved a sensitivity of 93.75%, a specificity of 100%, and an overall concordance of 97.86%. Compared with the validated results, it achieved a sensitivity of 97.96%, a specificity of 99.28%, an and overall concordance of 98.93% in fusion/rearrangement and Met exon skipping detection, which was superior to DNA-NGS. Compared to clinical testing, this assay demonstrated a sensitivity of 93.33%, a specificity of 100%, and an overall concordance rate of 97.93%. CONCLUSIONS This study substantiates that the targeted RNA-sequencing assay, based on probe hybridization capture, represents a superior detection technology platform for the application of drug targeting. It expeditiously and reliably provides all the requisite biomarkers for current NSCLC targeted therapies in a single-sample testing workflow, facilitating rapid clinical diagnosis and the formulation of rational treatment plans by clinicians.
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Affiliation(s)
- Ji Li
- Department of Pathology, Peking Union Medical College Hospital, 1 Shuai Fu Community, Dongcheng District, Beijing, 100000, China
| | - Xiaohua Shi
- Department of Pathology, Peking Union Medical College Hospital, 1 Shuai Fu Community, Dongcheng District, Beijing, 100000, China
| | - Hui Zhang
- Department of Pathology, Peking Union Medical College Hospital, 1 Shuai Fu Community, Dongcheng District, Beijing, 100000, China
| | - Xiaojing Lin
- Zhenyue Biotechnology Jiangsu Co., Ltd., Taizhou, Jiangsu, China
| | - Shan Zheng
- Zhenyue Biotechnology Jiangsu Co., Ltd., Taizhou, Jiangsu, China
| | - Weizhi Chen
- Zhenyue Biotechnology Jiangsu Co., Ltd., Taizhou, Jiangsu, China
| | - Yang Zhou
- Department of Pathology, Peking Union Medical College Hospital, 1 Shuai Fu Community, Dongcheng District, Beijing, 100000, China
| | - Zhiyong Liang
- Department of Pathology, Peking Union Medical College Hospital, 1 Shuai Fu Community, Dongcheng District, Beijing, 100000, China.
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Nicosia S, Lyberis P, Rudella S, Lausi PO, Sobrero S, Cristofori RC, Roffinella M, Fontana EC, Leo F, Ruffini E, Guerrera F. Prognostic Value of Single Nodal Zone Metastasis in Non-Small-Cell Lung Cancer-A Multi-Institutional Study. J Clin Med 2025; 14:2938. [PMID: 40363970 PMCID: PMC12072844 DOI: 10.3390/jcm14092938] [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: 01/24/2025] [Revised: 04/19/2025] [Accepted: 04/21/2025] [Indexed: 05/15/2025] Open
Abstract
Objectives: Lung cancer is the leading cause of cancer-related deaths worldwide and mediastinal lymph node involvement is an important negative prognostic factor. Nevertheless, the involvement of a single mediastinal nodal zone has been reported to have favorable outcomes. This study aims to assess whether the prognosis of non-small-cell lung cancer (NSCLC) with single-zone lymph node involvement varies by the affected lymph node zone. Methods: We retrospectively analyzed patients affected by NSCLC with a single lymph node zone involvement who underwent anatomical resection. The prognosis of patients was statistically compared based on the different affected lymph node zones. Results: A total of 135 patients were enrolled. All patients underwent anatomical lung resection and systematic lymph node dissection. Lymph node involvement was observed in 50 cases (37%) for the upper zone, 36 cases (27%) for the aorto-pulmonary (AP) zone, 41 cases (30%) for the subcarinal zone and 8 cases (6%) for the lower zone. The median follow-up was 37 months [ranging from 1 to 115 months]. Cancer recurrence was reported in 64 cases (52%) during this period. The 2-year and 4-year overall survival (OS) were 69% and 49%, respectively. The 2-year and 4-year relapse-free survival (RFS) were 55% and 41%. The OS and RFS change relating to the different involved lymph node zones (p < 0.01). Lower zone involvement predicts worse prognosis, upper zone and subcarinal zone better outcomes, and the AP zone involvement intermediate survival. Conclusions: The location of the affected lymph nodes appears to be an important prognostic factor in patients with NSCLC, with significant impacts on both OS and RFS. It may play a key role in the disease progression and patient survival by providing more personalized therapy.
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Affiliation(s)
- Samanta Nicosia
- Department of Surgical Sciences, University of Torino, Corso Dogliotti, 14, 10126 Torino, Italy; (P.L.); (P.O.L.); (E.R.); (F.G.)
- Department of Thoracic Surgery, AOU Città Della Salute e Della Scienze di Torino, 10126 Torino, Italy; (R.C.C.); (M.R.); (E.C.F.)
| | - Paraskevas Lyberis
- Department of Surgical Sciences, University of Torino, Corso Dogliotti, 14, 10126 Torino, Italy; (P.L.); (P.O.L.); (E.R.); (F.G.)
- Department of Thoracic Surgery, AOU Città Della Salute e Della Scienze di Torino, 10126 Torino, Italy; (R.C.C.); (M.R.); (E.C.F.)
| | - Stefano Rudella
- AOU San Luigi Gonzaga, Thoracic Surgery Division, Department of Oncology, University of Torino, 10093 Orbassano, Italy; (S.R.); (S.S.); (F.L.)
| | - Paolo Olivo Lausi
- Department of Surgical Sciences, University of Torino, Corso Dogliotti, 14, 10126 Torino, Italy; (P.L.); (P.O.L.); (E.R.); (F.G.)
- Department of Thoracic Surgery, AOU Città Della Salute e Della Scienze di Torino, 10126 Torino, Italy; (R.C.C.); (M.R.); (E.C.F.)
| | - Simona Sobrero
- AOU San Luigi Gonzaga, Thoracic Surgery Division, Department of Oncology, University of Torino, 10093 Orbassano, Italy; (S.R.); (S.S.); (F.L.)
| | - Riccardo Carlo Cristofori
- Department of Thoracic Surgery, AOU Città Della Salute e Della Scienze di Torino, 10126 Torino, Italy; (R.C.C.); (M.R.); (E.C.F.)
| | - Matteo Roffinella
- Department of Thoracic Surgery, AOU Città Della Salute e Della Scienze di Torino, 10126 Torino, Italy; (R.C.C.); (M.R.); (E.C.F.)
| | - Elisa Carla Fontana
- Department of Thoracic Surgery, AOU Città Della Salute e Della Scienze di Torino, 10126 Torino, Italy; (R.C.C.); (M.R.); (E.C.F.)
| | - Francesco Leo
- AOU San Luigi Gonzaga, Thoracic Surgery Division, Department of Oncology, University of Torino, 10093 Orbassano, Italy; (S.R.); (S.S.); (F.L.)
| | - Enrico Ruffini
- Department of Surgical Sciences, University of Torino, Corso Dogliotti, 14, 10126 Torino, Italy; (P.L.); (P.O.L.); (E.R.); (F.G.)
- Department of Thoracic Surgery, AOU Città Della Salute e Della Scienze di Torino, 10126 Torino, Italy; (R.C.C.); (M.R.); (E.C.F.)
| | - Francesco Guerrera
- Department of Surgical Sciences, University of Torino, Corso Dogliotti, 14, 10126 Torino, Italy; (P.L.); (P.O.L.); (E.R.); (F.G.)
- Department of Thoracic Surgery, AOU Città Della Salute e Della Scienze di Torino, 10126 Torino, Italy; (R.C.C.); (M.R.); (E.C.F.)
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Padinharayil H, Varghese J, Varghese PR, Wilson CM, George A. Small Extracellular Vesicle (sEV) Uptake from Lung Adenocarcinoma and Squamous Cell Carcinoma Alters T-Cell Cytokine Expression and Modulates Protein Profiles in sEV Biogenesis. Proteomes 2025; 13:15. [PMID: 40407494 PMCID: PMC12101295 DOI: 10.3390/proteomes13020015] [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: 01/23/2025] [Revised: 04/17/2025] [Accepted: 04/21/2025] [Indexed: 05/26/2025] Open
Abstract
BACKGROUND Despite advances in immunotherapy, non-small-cell lung carcinoma (NSCLC)'s clinical success is limited, possibly due to substantial immunological alterations in advanced cancer patients. This study examines the immunomodulatory effects of sEVs derived from lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) on T cells. METHODS SEVs were isolated from lung cancer cell lines and Jurkat-E6.1. SEV size and morphology were analyzed by NTA and TEM, respectively, while Western blotting confirmed sEV markers. SEV uptake was assessed, followed by resazurin assay, RNA isolation, quantification, cDNA preparation, RT-PCR, nano LC-MS, and bioinformatic analysis, before and after treating Jurkat-E6.1 cells with sEVs from A549 and SKMES1. RESULTS Cancer-derived sEVs were efficiently internalized by immune cells, reducing T-cell viability. The real-time PCR analysis showed downregulation of KI67, BCL2, BAX, TNFA, IL6, TGFβ, and IL10, suggesting reduced proliferation, dysregulated apoptosis, and impaired inflammatory and immunosuppressive signaling, and the upregulation of GZMB and IL2 suggests retained cytotoxic potential but possibly dysfunctional T-cell activation. Proteomic analysis revealed 39 differentially abundant proteins (DAPs) in ADC-treated T cells and 276 in SCC-treated T cells, with 19 shared DAPs. Gene Ontology (GO) analysis of these DAPs highlighted processes such as sEV biogenesis, metabolic pathways, and regulatory functions, with ADC sEVs influencing NAD metabolism, ECM binding, and oxidoreductase activity, while SCC sEVs affected mRNA stability, amino acid metabolism, and cadherin binding. The cytoplasmic colocalization suggests the presence of these proteins in the cellular and extracellular lumen, indicating the potential of further release of these proteins in the vesicles by T cells. CONCLUSION Lung cancer-derived sEVs regulate T-cell activities through immunoregulatory signaling. The molecular interactions between sEVs and immune cells can reveal novel tumor immune regulatory mechanisms and therapeutic targets.
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Affiliation(s)
- Hafiza Padinharayil
- Jubilee Mission Medical College & Research Institute, Thrissur 680005, Kerala, India; (H.P.); (P.R.V.)
- Department of Zoology, St. Thomas College, Kozhencherry, Pathanamthitta 689641, Kerala, India;
| | - Jinsu Varghese
- Department of Zoology, St. Thomas College, Kozhencherry, Pathanamthitta 689641, Kerala, India;
| | | | - Cornelia M. Wilson
- School of Psychology and Life Sciences, Canterbury Christ Church University, Kent CT1 1QU, UK
| | - Alex George
- Jubilee Mission Medical College & Research Institute, Thrissur 680005, Kerala, India; (H.P.); (P.R.V.)
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Nam SB, Choi JH, Lee GE, Kim JY, Lee MH, Yang G, Cho YY, Jeong HG, Bang G, Lee CJ. Extracts from Allium pseudojaponicum Makino Target STAT3 Signaling Pathway to Overcome Cisplatin Resistance in Lung Cancer. Mar Drugs 2025; 23:167. [PMID: 40278288 PMCID: PMC12028371 DOI: 10.3390/md23040167] [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: 03/20/2025] [Revised: 04/10/2025] [Accepted: 04/10/2025] [Indexed: 04/26/2025] Open
Abstract
Lung cancer, particularly non-small-cell lung cancer (NSCLC), remains a leading cause of cancer-related mortality, with cisplatin-based chemotherapy being a standard treatment. However, the development of chemoresistance significantly limits its efficacy, necessitating alternative therapeutic approaches. Here, we demonstrate the anticancer effects of the extracts of Allium pseudojaponicum Makino (APE), a salt-tolerant plant, in cisplatin-resistant NSCLC. Metabolite profiling using UPLC-Q-TOF-MSE identified 13 major compounds, predominantly alkaloids (71.65%) and flavonoids (8.81%), with key bioactive constituents such as lycorine (29.81%), tazettine (17.22%), and tricetin (8.19%). APE significantly inhibited cell viability in A549 and H460 cells, reducing viability to 38.6% (A549-Ctr), 37.2% (A549-CR), 28.4% (H460-Ctr), and 30.4% (H460-CR) at 40 µg/mL after 48 h. APE also suppressed colony formation by over 90% in both 2D and soft agar assays, while showing no cytotoxicity in normal human keratinocytes up to 80 µg/mL. Flow cytometry analysis revealed APE-induced G1 phase arrest, with the G1 population increasing from 50.4% to 56.6% (A549-Ctr) and 47.5% to 58.4% (A549-CR), accompanied by reduced S phase populations. This effect was associated with the downregulation of G1/S transition regulators, including cyclin D1, CDK4, cyclin E, and CDK2. Furthermore, proteomic analysis identified STAT3 signaling as a major target of APE; APE decreased phosphorylated STAT3 and c-Myc expression, and STAT3 knockdown phenocopied the effects of APE. These findings highlight the potential of APE as a natural product-based therapeutic strategy for overcoming cisplatin resistance in NSCLC.
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Affiliation(s)
- Soo-Bin Nam
- Biopharmaceutical Research Center, Korea Basic Science Institute (KBSI), Cheongju 28119, Republic of Korea; (S.-B.N.); (G.-E.L.)
- College of Pharmacy, The Catholic University of Korea, Bucheon 14662, Republic of Korea;
| | - Jung Hoon Choi
- Digital Omics Research Center, Korea Basic Science Institute (KBSI), Cheongju 28119, Republic of Korea; (J.H.C.); (J.Y.K.)
- College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea;
| | - Ga-Eun Lee
- Biopharmaceutical Research Center, Korea Basic Science Institute (KBSI), Cheongju 28119, Republic of Korea; (S.-B.N.); (G.-E.L.)
| | - Jin Young Kim
- Digital Omics Research Center, Korea Basic Science Institute (KBSI), Cheongju 28119, Republic of Korea; (J.H.C.); (J.Y.K.)
| | - Mee-Hyun Lee
- College of Korean Medicine, Dongshin University, Naju 58245, Republic of Korea;
| | - Gabsik Yang
- Department of Korean Medicine, College of Korean Medicine, Woosuk University, Jeonju 55338, Republic of Korea;
| | - Yong-Yeon Cho
- College of Pharmacy, The Catholic University of Korea, Bucheon 14662, Republic of Korea;
| | - Hye Gwang Jeong
- College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea;
| | - Geul Bang
- Digital Omics Research Center, Korea Basic Science Institute (KBSI), Cheongju 28119, Republic of Korea; (J.H.C.); (J.Y.K.)
| | - Cheol-Jung Lee
- Biopharmaceutical Research Center, Korea Basic Science Institute (KBSI), Cheongju 28119, Republic of Korea; (S.-B.N.); (G.-E.L.)
- Department of Bio-Analytical Science, University of Science and Technology (UST), Daejeon 34113, Republic of Korea
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Hao X, Liu Z, Ma F, Li T, Liu C, Wang N, Guan J, He N, Liu J, Lu S, Song H, Li J, Wen K. Exosome-Based Liquid Biopsy in Early Screening and Diagnosis of Cancers. Dose Response 2025; 23:15593258251344480. [PMID: 40444064 PMCID: PMC12120305 DOI: 10.1177/15593258251344480] [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: 11/07/2024] [Revised: 03/31/2025] [Accepted: 05/05/2025] [Indexed: 06/02/2025] Open
Abstract
Background: Liquid biopsy, analyzing the expression and variation of circulating tumor cell (CTC) or circulating tumor nucleic acid genes in peripheral blood, can obtain the information of tumorigenesis, metastasis and treatment, which has a potentially broader and complementary applications in the precision cancer medicine. Small vesicles, like exosomes which belongs to extracellular vesicles (EVs), which released by living cells into the vicinal surrounding biofluids, especially cells from carcinoma. Tumor-derived materials were contained by exosomes, totally including proteins, nucleic acid genes, and lipid, etcetera for instance metabolites. Besides, molecules which were synchronously belongings and carried on exosomal surface can tolerable provides crucial clues regarding their origin. Thus, classified the types of vesicles and enrich features from tissue-specific sources become presumably achieved. Therefore, exosomes and other EVs have emerged as a liquid biopsy platform for early screening and diagnosis of cancers, which constantaneously carry-over multitudinous surface molecules also throw clues regarding their origin. It is feasible to sort vesicles types, intake with approach channel to enrich the characteristics from tissue-specific origin. Based on the property that exosomes are remarkably stable in body fluids, which can amenity gathered in plasma or urine, it can be used for meticulous clinical evaluation particularly in the early stages of carcinoma. Therefore, exosomes have aroused immense interest in the study of biomarkers. Conclusions and Perspectives: This review aims to summarize the potential exosomal biomarkers especially exosomal miRNAs for exosome-based liquid biopsy in early screening and diagnostic of cancers, including lung cancer, breast cancer (BC), kidney cancer, prostate cancer (PCa), colorectal cancer (CRC), and summarizes the traditional and novel technologies for isolating exosomes and for detecting exosomal-based biomarkers, including exosomal proteins and exosomal nucleic acids. Finally, the limitations and prospects of exosome-based liquid biopsy in the early screening and diagnosis of cancers were discussed briefly.
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Affiliation(s)
- Xuying Hao
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
| | - Zihan Liu
- Medical College of Shanxi Datong University, China
| | - Feifei Ma
- School of Basic Medicine, Shandong Second Medical University, Weifang, China
- Department of Radiology, Shanting District People’s Hospital, Zaozhuang, China
| | - Tuo Li
- School of Basic Medicine, Shandong Second Medical University, Weifang, China
| | - Chengbin Liu
- School of Basic Medicine, Shandong Second Medical University, Weifang, China
| | - Ning Wang
- School of Basic Medicine, Shandong Second Medical University, Weifang, China
| | - Jiebing Guan
- School of Basic Medicine, Shandong Second Medical University, Weifang, China
| | - Ningning He
- State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin Institutes of Health Science, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Jiao Liu
- School of Basic Medicine, Shandong Second Medical University, Weifang, China
| | - Shujuan Lu
- Department of Radiology, Shanting District People’s Hospital, Zaozhuang, China
| | - Huijuan Song
- State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin Institutes of Health Science, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Jianguo Li
- School of Basic Medicine, Shandong Second Medical University, Weifang, China
| | - Kaixue Wen
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
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Raziq MF, Khan N, Manzoor H, Tariq HMA, Rafiq M, Rasool S, Kayani MUR, Huang L. Prioritizing gut microbial SNPs linked to immunotherapy outcomes in NSCLC patients by integrative bioinformatics analysis. J Transl Med 2025; 23:343. [PMID: 40098172 PMCID: PMC11916936 DOI: 10.1186/s12967-025-06370-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Accepted: 03/08/2025] [Indexed: 03/19/2025] Open
Abstract
BACKGROUND The human gut microbiome has emerged as a potential modulator of treatment efficacy for different cancers, including non-small cell lung cancer (NSCLC) patients undergoing immune checkpoint inhibitor (ICI) therapy. In this study, we investigated the association of gut microbial variations with response against ICIs by analyzing the gut metagenomes of NSCLC patients. METHODS Strain identification from the publicly available metagenomes of 87 NSCLC patients, treated with nivolumab and collected at three different timepoints (T0, T1, and T2), was performed using StrainPhlAn3. Variant calling and annotations were performed using Snippy and associations between microbial genes and genomic variations with treatment responses were evaluated using MaAsLin2. Supervised machine learning models were developed to prioritize single nucleotide polymorphisms (SNPs) predictive of treatment response. Structural bioinformatics approaches were employed using MUpro, I-Mutant 2.0, CASTp and PyMOL to access the functional impact of prioritized SNPs on protein stability and active site interactions. RESULTS Our findings revealed the presence of strains for several microbial species (e.g., Lachnospira eligens) exclusively in Responders (R) or Non-responders (NR) (e.g., Parabacteroides distasonis). Variant calling and annotations for the identified strains from R and NR patients highlighted variations in genes (e.g., ftsA, lpdA, and nadB) that were significantly associated with the NR status of patients. Among the developed models, Logistic Regression performed best (accuracy > 90% and AUC ROC > 95%) in prioritizing SNPs in genes that could distinguish R and NR at T0. These SNPs included Ala168Val (lpdA) in Phocaeicola dorei and Tyr233His (lpdA), Leu330Ser (lpdA), and His233Arg (obgE) in Parabacteroides distasonis. Lastly, structural analyses of these prioritized variants in objE and lpdA revealed their involvement in the substrate binding site and an overall reduction in protein stability. This suggests that these variations might likely disrupt substrate interactions and compromise protein stability, thereby impairing normal protein functionality. CONCLUSION The integration of metagenomics, machine learning, and structural bioinformatics provides a robust framework for understanding the association between gut microbial variations and treatment response, paving the way for personalized therapies for NSCLC in the future. These findings emphasize the potential clinical implications of microbiome-based biomarkers in guiding patient-specific treatment strategies and improving immunotherapy outcomes.
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Affiliation(s)
- Muhammad Faheem Raziq
- Department of Infectious Disease, Children'S Hospital, Zhejiang University School of Medicine, 3333 Binsheng Road, Binjiang District, 310052, Hangzhou, China
- Metagenomics Discovery Lab, School of Interdisciplinary Engineering & Sciences (SINES), National University of Sciences & Technology (NUST), Sector H-12, Islamabad, 44000, Pakistan
| | - Nadeem Khan
- Metagenomics Discovery Lab, School of Interdisciplinary Engineering & Sciences (SINES), National University of Sciences & Technology (NUST), Sector H-12, Islamabad, 44000, Pakistan
| | - Haseeb Manzoor
- Metagenomics Discovery Lab, School of Interdisciplinary Engineering & Sciences (SINES), National University of Sciences & Technology (NUST), Sector H-12, Islamabad, 44000, Pakistan
| | - Hafiz Muhammad Adnan Tariq
- Metagenomics Discovery Lab, School of Interdisciplinary Engineering & Sciences (SINES), National University of Sciences & Technology (NUST), Sector H-12, Islamabad, 44000, Pakistan
| | - Mehak Rafiq
- School of Interdisciplinary Engineering & Sciences (SINES), National University of Sciences & Technology (NUST), Sector H-12, Islamabad, 44000, Pakistan
| | - Shahzad Rasool
- School of Interdisciplinary Engineering & Sciences (SINES), National University of Sciences & Technology (NUST), Sector H-12, Islamabad, 44000, Pakistan
| | - Masood Ur Rehman Kayani
- Metagenomics Discovery Lab, School of Interdisciplinary Engineering & Sciences (SINES), National University of Sciences & Technology (NUST), Sector H-12, Islamabad, 44000, Pakistan.
| | - Lisu Huang
- Department of Infectious Disease, Children'S Hospital, Zhejiang University School of Medicine, 3333 Binsheng Road, Binjiang District, 310052, Hangzhou, China.
- National Clinical Research Center for Child Health, Children'S Hospital, Zhejiang University School of Medicine, 3333 Binsheng Road, Binjiang District, 310052, Hangzhou, China.
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9
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Dawood H, Nawaz M, Ilyas MU, Nazir T, Javed A. Attention-guided CenterNet deep learning approach for lung cancer detection. Comput Biol Med 2025; 186:109613. [PMID: 39753023 DOI: 10.1016/j.compbiomed.2024.109613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 12/13/2024] [Accepted: 12/21/2024] [Indexed: 02/20/2025]
Abstract
Lung cancer remains a significant health concern worldwide, prompting ongoing research efforts to enhance early detection and diagnosis. Prior studies have identified key challenges in existing approaches, including limitations in feature extraction, interpretability, and computational efficiency. In response, this study introduces a novel deep learning (DL) framework, termed the Improved CenterNet approach, tailored specifically for lung cancer detection. The primary importance of this work lies in its innovative integration of ResNet-34 with an attention mechanism within the CenterNet architecture, addressing critical limitations identified in previous studies. By augmenting the base network with an attention mechanism, our framework offers improved feature extraction capabilities, enabling the model to learn relevant patterns associated with lung cancer amidst complex backgrounds and varying environmental conditions. This enhancement facilitates more accurate and interpretable predictions while reducing computational complexity and inference times. Through extensive experimental evaluations conducted on standard datasets, our proposed approach demonstrates promising results, highlighting its potential to advance the field of lung cancer detection and diagnosis. Specifically, we have acquired the precision, recall, and F1-Score of 99.89 %, 99.82 %, and 99.85 % on the LUNA-16 dataset, and 98.33 %, 98.02 %, and 98.17 % for the Kaggle data sample, respectively which is showing the efficacy of our approach. One limitation of the work is that it cannot effectively locate the samples with intense light variations. Therefore, future research work is focused on overcoming this challenge.
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Affiliation(s)
- Hussain Dawood
- School of Computing, Skyline University College, Sharjah, United Arab Emirates
| | - Marriam Nawaz
- Department of Software Engineering, University of Engineering and Technology-Taxila, 47050, Punjab, Pakistan
| | - Muhammad U Ilyas
- School of Computer Science, University of Birmingham, Dubai, United Arab Emirates
| | - Tahira Nazir
- Department of Software Engineering and Computer Science, Riphah International University, Gulberg Green Campus Islamabad, Pakistan
| | - Ali Javed
- Department of Software Engineering, University of Engineering and Technology-Taxila, 47050, Punjab, Pakistan.
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10
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Boyacıoğlu Ö, Varan C, Bilensoy E, Aykut ZG, Reçber T, Nemutlu E, Kılıç N, Korkusuz P. A novel injectable nanotherapeutic platform increasing the bioavailability and anti-tumor efficacy of Arachidonylcyclopropylamide on an ectopic non-small cell lung cancer xenograft model: A randomized controlled trial. Int J Pharm 2025; 670:125153. [PMID: 39746587 DOI: 10.1016/j.ijpharm.2024.125153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 12/29/2024] [Accepted: 12/29/2024] [Indexed: 01/04/2025]
Abstract
Rapid progressing non-small cell lung adenocarcinoma (NSCLC) decreases treatment success. Cannabinoids emerge as drug candidates for NSCLC due to their anti-tumoral capabilities. We previously reported the controlled release of Arachidonylcyclopropylamide (ACPA) selectively targeting cannabinoid 1 (CB1) receptor in NSCLC cells in vitro. Hydrophobic polymers like polycaprolactone (PCL) offer prolonged circulation time and slower drug clearance which is suitable for hydrophobic molecules like ACPA. Thus, the extended circulation time with enhanced bioavailability and half-life of nanoparticular ACPA is crucial for its therapeutic performance in the tumor area. We assumed that a novel high technology-controlled release system increasing the bioavailability of ACPA compared to free ACPA could be transferred to the clinic when validated in vivo. Plasma profile of ACPA and ACPA-loaded PCL-based nanomedicine by LC-MS/MS and complete blood count (CBC) was assessed in wild-type Balb/c mice. Tumor growth in nanomedicine-applied NSCLC-induced athymic nude mice was assessed using bioluminescence imaging (BLI) and caliper measurements, histomorphometry, immunohistochemistry, TUNEL assay, and Western blot on days 7-21. Injectable NanoACPA increased its systemic exposure to tissues 5.5 times and maximum plasma concentration 6 times higher than free ACPA by substantially improving bioavailability. The potent effect of NanoACPA lasted for at least two days on ectopic NSCLC model through Akt/PI3K, Ras/MEK/Erk, and JNK pathways that diminished Ki-67 proliferative and promoted TUNEL apoptotic cell scores on days 7-21. The output reveals that NanoACPA platform could be a chemotherapeutic for NSCLC in the clinic following scale-up GLP/GMP-based phase trials, owing to therapeutic efficacy at a safe low dose window.
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Affiliation(s)
- Özge Boyacıoğlu
- Hacettepe University, Graduate School of Science and Engineering, Department of Bioengineering, 06800, Beytepe, Ankara, Turkey; Atılım University, Faculty of Medicine, Department of Medical Biochemistry, 06830, Gölbaşı, Ankara, Turkey
| | - Cem Varan
- Hacettepe University, Graduate School of Science and Engineering, Department of Nanotechnology and Nanomedicine, 06800, Beytepe, Ankara, Turkey
| | - Erem Bilensoy
- Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Technology, 06100, Sıhhiye, Ankara, Turkey
| | - Zaliha Gamze Aykut
- Bilkent University, Faculty of Science, Department of Molecular Biology and Genetics, 06800, Cankaya, Ankara, Turkey
| | - Tuba Reçber
- Hacettepe University, Faculty of Pharmacy, Department of Analytical Chemistry, 06100, Sıhhiye, Ankara, Turkey
| | - Emirhan Nemutlu
- Hacettepe University, Faculty of Pharmacy, Department of Analytical Chemistry, 06100, Sıhhiye, Ankara, Turkey
| | - Nedret Kılıç
- Atılım University, Faculty of Medicine, Department of Medical Biochemistry, 06830, Gölbaşı, Ankara, Turkey
| | - Petek Korkusuz
- Hacettepe University, Faculty of Medicine, Department of Histology and Embryology, 06100, Sıhhiye, Ankara, Turkey; METU MEMS Center, 06530, Ankara, Turkey.
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11
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Kurian R, Wang H. Prodrugs in Oncology: Bioactivation and Impact on Therapeutic Efficacy and Toxicity. Int J Mol Sci 2025; 26:988. [PMID: 39940757 PMCID: PMC11816641 DOI: 10.3390/ijms26030988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 01/16/2025] [Accepted: 01/20/2025] [Indexed: 02/16/2025] Open
Abstract
A prodrug is a molecule that lacks pharmacological activity, but upon enzymatic bioactivation, it can generate a therapeutically active molecule. The primary reason behind the design of a prodrug is to help circumvent challenges associated with the physicochemical properties of a drug molecule, such as solubility, absorption, distribution, and instability. Chemotherapy has been at the forefront of cancer treatment for over 70 years due to its ability to target rapidly proliferating tumor cells. However, a major concern with conventional chemotherapy is the lack of selectivity and its associated side toxicity, which can severely impact patients' quality of life. In oncology, prodrugs have been explored to enhance the bioavailability, improve efficacy, and minimize systemic toxicity of chemotherapeutic agents. Prodrugs activated by enzymes unique to a tumor microenvironment can significantly increase targeted delivery of chemotherapeutic drugs. This review aims to highlight commonly used chemotherapeutic prodrugs, including both alkylating and non-alkylating agents, and discuss their clinical relevance, mechanisms of bioactivation, and toxicity concerns.
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Affiliation(s)
| | - Hongbing Wang
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, USA;
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12
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Tesema GA, Stirling RG, Wah W, Tessema ZT, Heritier S, Earnest A. Geographic variation in delay to surgical treatment among non-small cell lung cancer patients. Lung Cancer 2025; 199:108077. [PMID: 39793326 DOI: 10.1016/j.lungcan.2024.108077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 12/02/2024] [Accepted: 12/30/2024] [Indexed: 01/13/2025]
Abstract
OBJECTIVES Delayed surgery is significantly associated with an increased risk of disease progression and adverse outcomes in lung cancer. Evidence is available on the variation in delayed surgical treatment among patients with Non-Small Cell Lung Cancer (NSCLC). However, the relative contribution of patient- and area-level risk factors to the geographic patterns of delayed surgery in patients with NSCLC is poorly understood. Therefore, we aimed to explore the geographic variation in delay to surgical treatment among patients with NSCLC. MATERIALS AND METHODS This study utilized data from the Victorian Lung Cancer Registry (VLCR) and the Australian Bureau of Statistics (ABS). A total of 3,088 patients with NSCLC who had undergone surgery were included. We applied a Bayesian spatial multilevel model incorporating spatially structured and unstructured random effects to examine patient and area-level risk factors associated with delays to surgical treatment. Model comparison was conducted using the Deviance Information Criterion (DIC). RESULTS Over one-third (40.45 %) of NSCLC patients experienced delayed surgical treatment. Significant geographic variation in delayed surgical treatment among NSCLC patients across Local Government Areas (LGAs) was observed. Factors significantly associated with higher odds of delayed surgical treatment included clinical stage II (AOR = 1.56, 95 % CrI: 1.26-1.92), stage III (AOR = 1.90, 95 % CrI: 1.46-2.47), stage IV (AOR = 2.04, 95 % CrI: 1.15-3.61), treatment at inner regional hospitals (AOR = 2.86, 95 % CrI: 2.17-3.70), presence of comorbidities (AOR = 1.19, 95 % CrI: 1.02-1.40), and diagnosis during the COVID-19 pandemic (AOR = 1.32, 95 % CrI: 1.10-1.57). CONCLUSIONS This study highlights the need to improve the treatment pathway for patients with NSCLC by reducing the time between diagnosis and surgery. Future targeted initiatives are essential to promote timely surgeries for NSCLC patients, especially in high-need areas.
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Affiliation(s)
- Getayeneh Antehunegn Tesema
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia; Department of Epidemiology and Biostatistics, Institute of Public Health, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Rob G Stirling
- Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne 3168, Australia; Department of Respiratory Medicine, Alfred Health, Melbourne 3004, Australia
| | - Win Wah
- Monash Centre for Occupational and Environmental Health, School of Public Health and Preventive Medicine, Monash University, 553St Kilda Road, Melbourne, Victoria 3004, Australia
| | - Zemenu Tadesse Tessema
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia; Department of Epidemiology and Biostatistics, Institute of Public Health, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Stephane Heritier
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
| | - Arul Earnest
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.
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13
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Geng H, Xue Y, Yan B, Lu Z, Yang H, Li P, Zhou J. Network Pharmacology and Molecular Docking Study on the Mechanism of the Therapeutic Effect of Strychni Semen in NSCLC. Biol Proced Online 2024; 26:33. [PMID: 39736533 DOI: 10.1186/s12575-024-00259-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 12/18/2024] [Indexed: 01/01/2025] Open
Abstract
Strychni Semen, characterized by its bitter taste and warm properties, has been confirmed to possess anti-tumor properties. However, the molecular mechanism of Strychni Semen in treating non-small cell lung cancer (NSCLC) needs further study. This study aimed to explore the molecular mechanism of Strychni Semen in treating NSCLC based on network pharmacology and molecular docking. The active components and targets of Strychni Semen were retrieved from the TCMSP, supplemented by the HERB database and the related literature. NSCLC-related targets were retrieved from the GeneCards, OMIM and DisGenet databases. The intersection targets of Strychni Semen in treating NSCLC were obtained via an online platform. The Protein-Protein Interaction (PPI) network was subsequently constructed to deeply analyse the interrelationship of the intersection targets via the String database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were carried out via the Metascape database. The interactive networks between Strychni Semen and NSCLC were constructed via Cytoscape 3.9.1. Molecular docking detected interactions between the key components and the core targets. The core targets were validated via GEO datasets. 21 active components and 67 targets were identified, with 47 associated with NSCLC. The key active components were Stigmasterol, IcarideA, 2-Hydroxymethylanthraquinone, (+)-catechin, (2R)-5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one, (S)-Stylopine, Brucine and Isobrucine. The core targets were PTGS2, NR3C1, ESR1, CASP3 and PRKACA. Molecular docking revealed that these compounds undergo strong binding affinity with the core genes. GEO database indicated that PTGS2 was the most promising core target. In addition, Strychni Semen's effects on NSCLC involved mainly the Calcium pathway, the Estrogen pathway, and the cGMP-PKG and cAMP pathways. This study visually demonstrated the mechanism of the therapeutic effect of Strychni Semen in NSCLC through multiple components, targets and pathways which provides a basis for clinical treatment and further experimental research.
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Affiliation(s)
- He Geng
- Department of Radiation Oncology, Huaian Hospital of Huaian City, Huaian Cancer Hospital, Huaian, Jiangsu, China
| | - Yujie Xue
- Department of Pathology, Affiliated Huaian NO. 1 People's Hospital of Nanjing Medical University, Huaian, Jiangsu, China
| | - Binghua Yan
- Department of Radiation Oncology, Huaian Hospital of Huaian City, Huaian Cancer Hospital, Huaian, Jiangsu, China
| | - Zhaoxue Lu
- Department of Radiation Oncology, Huaian Hospital of Huaian City, Huaian Cancer Hospital, Huaian, Jiangsu, China
| | - Hengjin Yang
- Department of Radiation Oncology, Huaian Hospital of Huaian City, Huaian Cancer Hospital, Huaian, Jiangsu, China
| | - Peng Li
- Department of Radiation Oncology, Huaian Hospital of Huaian City, Huaian Cancer Hospital, Huaian, Jiangsu, China.
| | - Jundong Zhou
- Department of Radiation Oncology, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, Jiangsu, China.
- Suzhou Cancer Center Core Laboratory, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, Jiangsu, China.
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14
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Helmy MW, Youssef MH, Yamari I, Amr A, Moussa FI, El Wakil A, Chtita S, El-Samad LM, Hassan MA. Repurposing of sericin combined with dactolisib or vitamin D to combat non-small lung cancer cells through computational and biological investigations. Sci Rep 2024; 14:27034. [PMID: 39505930 PMCID: PMC11541877 DOI: 10.1038/s41598-024-76947-0] [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: 07/16/2024] [Accepted: 10/17/2024] [Indexed: 11/08/2024] Open
Abstract
This study aims to repurpose sericin in combating non-small lung cancer cells (A549 and H460) by combining it with dactolisib or vitamin D to reduce the dose of dactolisib and boost the anticancer effectiveness of dactolisib and vitamin D. Therefore, the binding affinities of individual and combined drugs were examined using in silico and protein-protein interaction studies, targeting NF-κB, Cyclin D1, p-AKT, and VEGF1 proteins. The findings manifested remarkable affinities for combinatorial drugs compared to individual compounds. To substantiate these findings, the combined IC50 for each combination (sericin + dactolisib and sericin + vitamin D) were determined, reporting 31.9 and 41.8 µg/ml, respectively, against A549 cells and 47.9 and 55.3 µg/ml, respectively, against H460 cells. Furthermore, combination indices were assessed to lower the doses of each drug. Interestingly, in vitro results exhibited marked diminutions in NF-κB, Cyclin D1, p-AKT, and VEGF1 after treatment with sericin + dactolisib and sericin + vitamin D compared to control lung cancer cells and those treated with a single drug. Moreover, A549 and H460 cells treated with both combinations demonstrated augmented caspase-3 levels, implying substantial apoptotic activity. Altogether, these results accentuated the prospective implementation of sericin in combination with dactolisib and vitamin D at low doses to preclude lung cancer cell proliferation.
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Affiliation(s)
- Maged W Helmy
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Damanhour University, 22511, Damanhour, Egypt
| | - Mariam H Youssef
- Department of Zoology, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Imane Yamari
- Laboratory of Analytical and Molecular Chemistry, Faculty of Sciences Ben M'Sik, Hassan II University of Casablanca, P. O. Box 7955, Casablanca, Morocco
| | - Alaa Amr
- Department of Zoology, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Farouzia I Moussa
- Department of Zoology, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Abeer El Wakil
- Department of Biological and Geological Sciences, Faculty of Education, Alexandria University, Alexandria, Egypt
| | - Samir Chtita
- Laboratory of Analytical and Molecular Chemistry, Faculty of Sciences Ben M'Sik, Hassan II University of Casablanca, P. O. Box 7955, Casablanca, Morocco
| | - Lamia M El-Samad
- Department of Zoology, Faculty of Science, Alexandria University, Alexandria, Egypt.
| | - Mohamed A Hassan
- Protein Research Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), City of Scientific Research and Technological Applications (SRTA-City), New Borg El-Arab City, 21934, Alexandria, Egypt.
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15
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Chang SC, Wei YF, Chen CY, Lai YC, Hu PW, Hung JC, Chang CY. Profiling Cell-Free DNA from Malignant Pleural Effusion for Oncogenic Driver Mutations in Patients with Treatment-Naive Stage IV Adenocarcinoma: A Multicenter Prospective Study. Mol Diagn Ther 2024; 28:803-810. [PMID: 39147938 PMCID: PMC11512990 DOI: 10.1007/s40291-024-00736-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/31/2024] [Indexed: 08/17/2024]
Abstract
INTRODUCTION Comprehensive next-generation sequencing (NGS) of non-small-cell lung cancer specimens can identify oncogenic driver mutations and their corresponding targeted therapies. Plasma cell-free DNA (cfDNA) genotyping is easy to perform; however, false negatives cannot be overlooked. We explored malignant pleural effusion (MPE), a rich source of cfDNA, as a non-inferior alternative to tumor tissues for genotyping. METHODS We conducted a prospective trial including 39 patients with newly diagnosed stage IV lung adenocarcinoma who presented with MPE. Tissue tests matching hotspot variants, including EGFR, ALK, and ROS1, were compared with the AlphaLiquid100 of PE-cfDNA. RESULTS Among the 39 PE-cfDNA samples successfully sequenced, 32 (82.1%) had a PE cell-block tumor content of < 10%. Standard tissue or cell-block testing for EGFR, ALK, and ROS1 identified 20 mutations (51.3%), whereas PE cfDNA identified 25 mutations (64.1%). Five EGFR mutations were observed in PE cfDNA but not in Cobas EGFR owing to coverage or insufficient tumor content issues. The overall rate of oncogenic mutations identified in the PE cfDNA was 92.3%, and the mutation distribution was as follows: even with a very low cfDNA input, high detection rates could be achieved. Otherwise, most patients harbored co-mutations. Comparison of pleural fluid NGS with traditional testing revealed differences in accuracy. We also followed up with patients with EGFR-sensitizing mutations who had a treatment response rate of 97.2% after 3 months. CONCLUSIONS Genotyping of MPE supernatant cfDNA is feasible in clinical practice, in addition to plasma and tumor testing, to improve diagnostic yield and extend patients' benefit from targeted therapies.
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Affiliation(s)
- Shih-Chieh Chang
- Division of Chest Medicine, Department of Internal Medicine, National Yang Ming Chiao Tung University Hospital, Yi-Lan, Taiwan
| | - Yu-Feng Wei
- School of Medicine for International Students, College of Medicine, I-Shou University, Kaohsiung, Taiwan
- Department of Internal Medicine, E-Da Cancer Hospital, I-Shou University, Kaohsiung, Taiwan
| | - Chung-Yu Chen
- Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin County, Taiwan
| | - Yi-Chun Lai
- Division of Chest Medicine, Department of Internal Medicine, National Yang Ming Chiao Tung University Hospital, Yi-Lan, Taiwan
| | - Po-Wei Hu
- Division of Chest Medicine, Department of Internal Medicine, National Yang Ming Chiao Tung University Hospital, Yi-Lan, Taiwan
| | - Jui-Chi Hung
- Division of Chest Medicine, Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan
| | - Cheng-Yu Chang
- Division of Chest Medicine, Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan.
- College of Electrical and Communication Engineering, Taoyuan City, Taiwan.
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16
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Kowalski DM, Zaborowska-Szmit M, Bryl M, Byszek A, Dziedzic DA, Jaśkiewicz P, Langfort R, Krzakowski M, Orłowski T, Ramlau R, Szmit S. The Detailed Analysis of Polish Patients with Non-Small Cell Lung Cancer Through Insights from Molecular Testing (POL-MOL Study). Int J Mol Sci 2024; 25:11354. [PMID: 39518907 PMCID: PMC11547071 DOI: 10.3390/ijms252111354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 10/16/2024] [Accepted: 10/17/2024] [Indexed: 11/16/2024] Open
Abstract
Molecular testing is recommended in patients with metastatic non-small cell lung cancer (NSCLC), but the extent of its use in Poland is unknown. The aim of the POL-MOL study was to investigate the frequency of using molecular testing in Polish patients with NSCLC. The invited Polish oncologists completed two questionnaires, and data for 1001 patients undergoing systemic treatment for NSCLC were collected. The use of molecular tests for the following genetic mutations was recorded: EGFR (del19, sub21), EGFR (other than del19/sub21), EGFR T790M, ALK (expression and rearrangement), RET, NTRK, ROS1, BRAF, HER2, and MET, as well as for immunochemical assessment of programmed cell death ligand 1 (PD-L1). Thanks to the weighting procedure, the results are representative of the population of Polish patients treated for NSCLC. Molecular tests were applied in 78% of patients with NSCL, 70% of patients with NSCLC not otherwise specified, and in 12% of patients with squamous cell carcinoma of the lung. The frequency of application increased with disease stage in all groups. In patients with squamous cell carcinoma, approximately 30% of tests for EGFR, ALK, and RET mutations were positive, which confirms the importance of testing at least a preselected subgroup of patients.
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Affiliation(s)
- Dariusz M. Kowalski
- Department of Lung Cancer and Thoracic Tumors, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; (D.M.K.); (M.Z.-S.); (P.J.); (M.K.)
- Polish Lung Cancer Study Group, 01-138 Warsaw, Poland (A.B.); (D.A.D.); (R.L.); (T.O.); (R.R.)
| | - Magdalena Zaborowska-Szmit
- Department of Lung Cancer and Thoracic Tumors, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; (D.M.K.); (M.Z.-S.); (P.J.); (M.K.)
- Polish Lung Cancer Study Group, 01-138 Warsaw, Poland (A.B.); (D.A.D.); (R.L.); (T.O.); (R.R.)
| | - Maciej Bryl
- Polish Lung Cancer Study Group, 01-138 Warsaw, Poland (A.B.); (D.A.D.); (R.L.); (T.O.); (R.R.)
- Centre of Pulmonology and Thoracic Surgery, 60-569 Poznań, Poland
| | - Agnieszka Byszek
- Polish Lung Cancer Study Group, 01-138 Warsaw, Poland (A.B.); (D.A.D.); (R.L.); (T.O.); (R.R.)
| | - Dariusz Adam Dziedzic
- Polish Lung Cancer Study Group, 01-138 Warsaw, Poland (A.B.); (D.A.D.); (R.L.); (T.O.); (R.R.)
- Department of Thoracic Surgery, National Institute of Tuberculosis and Pulmonary Disease, 01-138 Warsaw, Poland
| | - Piotr Jaśkiewicz
- Department of Lung Cancer and Thoracic Tumors, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; (D.M.K.); (M.Z.-S.); (P.J.); (M.K.)
- Polish Lung Cancer Study Group, 01-138 Warsaw, Poland (A.B.); (D.A.D.); (R.L.); (T.O.); (R.R.)
| | - Renata Langfort
- Polish Lung Cancer Study Group, 01-138 Warsaw, Poland (A.B.); (D.A.D.); (R.L.); (T.O.); (R.R.)
- Department of Pathology, National Institute of Tuberculosis and Pulmonary Disease, 01-138 Warsaw, Poland
| | - Maciej Krzakowski
- Department of Lung Cancer and Thoracic Tumors, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; (D.M.K.); (M.Z.-S.); (P.J.); (M.K.)
- Polish Lung Cancer Study Group, 01-138 Warsaw, Poland (A.B.); (D.A.D.); (R.L.); (T.O.); (R.R.)
| | - Tadeusz Orłowski
- Polish Lung Cancer Study Group, 01-138 Warsaw, Poland (A.B.); (D.A.D.); (R.L.); (T.O.); (R.R.)
- Department of Thoracic Surgery, National Institute of Tuberculosis and Pulmonary Disease, 01-138 Warsaw, Poland
| | - Rodryg Ramlau
- Polish Lung Cancer Study Group, 01-138 Warsaw, Poland (A.B.); (D.A.D.); (R.L.); (T.O.); (R.R.)
- Institute of Oncology, Poznan University of Medical Sciences, 60-514 Poznań, Poland
| | - Sebastian Szmit
- Polish Lung Cancer Study Group, 01-138 Warsaw, Poland (A.B.); (D.A.D.); (R.L.); (T.O.); (R.R.)
- Department of Cardio-Oncology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland
- Department of Cancer Diagnostics and Cardio-Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland
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17
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Chen Y, Ma Y, Wu H, Wei X, Xu Z, Wang Q. Examining the relationship between preoperative nutritional and symptom assessment and postoperative atrial fibrillation in esophageal squamous cell carcinoma patients: a retrospective cohort study. BMC Surg 2024; 24:298. [PMID: 39385162 PMCID: PMC11463059 DOI: 10.1186/s12893-024-02609-7] [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: 02/16/2024] [Accepted: 10/01/2024] [Indexed: 10/11/2024] Open
Abstract
OBJECTIVE The study aimed to examine the relationship between preoperative nutritional status, symptom burden, and the occurrence of postoperative atrial fibrillation in Esophageal Squamous Cell Carcinoma patients. METHODS The study, conducted in the Department of Thoracic Surgery at the Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, applied the NRS 2002, SGA and MSAS scoring systems as measures of nutritional status and symptom occurrence in patients diagnosed with ESCC. Univariate and multivariate logistic regression analysis were performed to evaluate the association between nutritional scores, symptom scores, and postoperative complications. RESULTS The research found a significant correlation between high MSAS scores and postoperative atrial fibrillation. Patients with high symptom burden also tended to have nutritional risk or malnutrition according to the NRS2002 and SGA scores. CONCLUSION There is a need for healthcare providers to pay attention to ESCC patients' physical and psychological symptoms. Close monitoring of nutritional status and timely nutritional interventions should be integrated into these patients' care plans as they have been found to be related to postoperative complications such as atrial fibrillation.
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Affiliation(s)
- Yunyun Chen
- Department of Thoracic Surgery, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, 223300, China
| | - Yan Ma
- Department of Thoracic Surgery, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, 223300, China
| | - Haiyan Wu
- Department of Thoracic Surgery, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, 223300, China
| | - Xinqi Wei
- Department of Thoracic Surgery, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, 223300, China
| | - Zhiyun Xu
- Department of Thoracic Surgery, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, 223300, China.
| | - Qingmei Wang
- Department of Thoracic Surgery, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, 223300, China.
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18
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Delgado Y, Torres-Sanchez A, Perez D, Torres G, Estrada S, Ortiz Alvelo N, Vega J, Santos L, Torres A, Madera BA, Ferrer-Acosta Y. Deferasirox's Anti-Chemoresistance and Anti-Metastatic Effect on Non-Small Cell Lung Carcinoma. Biomedicines 2024; 12:2272. [PMID: 39457585 PMCID: PMC11505511 DOI: 10.3390/biomedicines12102272] [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: 09/07/2024] [Revised: 09/27/2024] [Accepted: 09/30/2024] [Indexed: 10/28/2024] Open
Abstract
Clinically approved iron chelators, originally designed to address iron overload disorders, have emerged as potential anticancer agents. Deferasirox (Def), a tridentate iron chelator, has demonstrated antiproliferative effects in cancer. Background/Objectives: This study aims to elucidate the mechanism of action of Def and its impact on non-small cell lung carcinoma (NSCLC). Methods: NSCLC A549 cells were treated with Def to assess cytotoxicity, the effect on nuclear and mitochondrial pathways, and iron-containing proteins and genes to evaluate anti-metastasis and chemoresistance. A lung carcinoma mouse model was used for in vivo studies. Results: Our findings revealed that Def induced cytotoxicity, effectively chelated intracellular iron, and triggered apoptosis through the increase in phosphatidylserine externalization and caspase 3 activity. Additionally, Def caused G0/G1 cell cycle arrest by downregulating the ribonucleotide reductase catalytic subunit. Furthermore, Def perturbed mitochondrial function by promoting the production of reactive oxygen species and the inhibition of glutathione as a measurement of ferroptosis activation. Def demonstrated inhibitory effects on cell migration in scratch assays, which was supported by the upregulation of n-myc downstream-regulated gene 1 and downregulation of the epidermal growth factor receptor protein. Also, Def downregulated one of the main markers of chemoresistance, the ABCB1 gene. In vivo experiments using a lung carcinoma mouse model showed that Def treatment did not affect the animal's body weight and showed a significant decrease in tumor growth. Conclusions: This investigation lays the groundwork for unraveling Def action's molecular targets and mechanisms in lung carcinoma, particularly within iron-related pathways, pointing out its anti-metastasis and anti-chemoresistance effect.
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Affiliation(s)
- Yamixa Delgado
- Biochemistry & Pharmacology Department, San Juan Bautista School of Medicine, Caguas, PR 00725, USA; (D.P.); (G.T.); (N.O.A.); (J.V.); (A.T.)
| | - Anamaris Torres-Sanchez
- Biology Department, University of Puerto Rico-Rio Piedras, San Juan, PR 00925, USA; (A.T.-S.); (S.E.)
| | - Daraishka Perez
- Biochemistry & Pharmacology Department, San Juan Bautista School of Medicine, Caguas, PR 00725, USA; (D.P.); (G.T.); (N.O.A.); (J.V.); (A.T.)
| | - Grace Torres
- Biochemistry & Pharmacology Department, San Juan Bautista School of Medicine, Caguas, PR 00725, USA; (D.P.); (G.T.); (N.O.A.); (J.V.); (A.T.)
| | - Sthephanie Estrada
- Biology Department, University of Puerto Rico-Rio Piedras, San Juan, PR 00925, USA; (A.T.-S.); (S.E.)
| | - Natalia Ortiz Alvelo
- Biochemistry & Pharmacology Department, San Juan Bautista School of Medicine, Caguas, PR 00725, USA; (D.P.); (G.T.); (N.O.A.); (J.V.); (A.T.)
| | - Jaisy Vega
- Biochemistry & Pharmacology Department, San Juan Bautista School of Medicine, Caguas, PR 00725, USA; (D.P.); (G.T.); (N.O.A.); (J.V.); (A.T.)
| | - Laurie Santos
- Biomedical Graduate Program, Universidad Central del Caribe, Bayamón, PR 00960, USA;
| | - Aracelis Torres
- Biochemistry & Pharmacology Department, San Juan Bautista School of Medicine, Caguas, PR 00725, USA; (D.P.); (G.T.); (N.O.A.); (J.V.); (A.T.)
| | - Bismark A. Madera
- Molecular Sciences Research Center, University of Puerto Rico, San Juan, PR 00926, USA;
| | - Yancy Ferrer-Acosta
- Department of Anatomy and Neurobiology, School of Medicine, University of Puerto Rico, Medical Sciences Campus, San Juan, PR 00936, USA;
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19
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Lv L, Song K, Xiao Y, Zheng J, Zhang W, Li L, Wei Y, Chen H, He Y, Guo Z, Nie S. Design, synthesis and anticancer activity of β-carboline based pseudo-natural products by inhibiting AKT/mTOR signaling pathway. Bioorg Chem 2024; 151:107648. [PMID: 39032406 DOI: 10.1016/j.bioorg.2024.107648] [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: 03/14/2024] [Revised: 07/12/2024] [Accepted: 07/14/2024] [Indexed: 07/23/2024]
Abstract
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and remains the leading cause of cancer deaths. Much progress has been made to treat NSCLC, however, only limited patients can benefit from current treatments. Thus, more efforts are needed to pursue novel molecular modalities for NSCLC treatment. It was demonstrated that pseudo-natural products (PNP) are a critical source for antitumor drug discovery. Herein, we describe a CH activation protocol for the expedient construction of a focused library utilizing the PNP rational design strategy. This protocol features a rhodium-catalyzed CH activation/ [4+2] annulation reaction between N-OAc-indole-2-carboxamide and alkynyl quinols, enabling facile access to diverse quinol substituted β-carboline derivatives (31 examples). The anticancer activities were assessed in vitro against NSCLC cell line A549, yielding a potent antiproliferative β-carboline derivative (8r) with an IC50 value of 0.8 ± 0.1 µM. Further investigation revealed that this compound could decrease the expression of Caspase 3, and increase the expression of autophagic protein Cyclin B1, thus markedly inducing autophagy and apoptosis. Mechanistic study suggested that 8r could be a potent anti-NSCLC agent through the AKT/mTOR signaling pathway in A549 cells. Moreover, the anticancer activities were also assessed against three other cancer cell lines, and 8r exhibits a broader inhibitory effect on cell proliferation in all cancer cell lines tested. These results indicated that carboline-based PNPs show great potential to induce cell autophagy and apoptosis, which serve as good leads for further drug discovery.
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Affiliation(s)
- Lijie Lv
- Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), Institute of Life Sciences & Department of Urology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
| | - Kunlin Song
- Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), Institute of Life Sciences & Department of Breast and Thyroid Surgery, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
| | - Yijie Xiao
- Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), Institute of Life Sciences & Department of Urology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
| | - Jia Zheng
- Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), Institute of Life Sciences & Department of Urology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
| | - Wei Zhang
- Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), Institute of Life Sciences & Department of Breast and Thyroid Surgery, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
| | - Linfeng Li
- Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), Institute of Life Sciences & Department of Breast and Thyroid Surgery, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
| | - Yue Wei
- Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), Institute of Life Sciences & Department of Breast and Thyroid Surgery, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
| | - Hao Chen
- State Key Laboratory of Chemical Biology, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Yi He
- Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), Institute of Life Sciences & Department of Urology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China; College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.
| | - Zufeng Guo
- Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), Institute of Life Sciences & Department of Breast and Thyroid Surgery, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China; College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.
| | - Shenyou Nie
- Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), Institute of Life Sciences & Department of Urology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China; College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.
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20
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Reina C, Šabanović B, Lazzari C, Gregorc V, Heeschen C. Unlocking the future of cancer diagnosis - promises and challenges of ctDNA-based liquid biopsies in non-small cell lung cancer. Transl Res 2024; 272:41-53. [PMID: 38838851 DOI: 10.1016/j.trsl.2024.05.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 04/29/2024] [Accepted: 05/30/2024] [Indexed: 06/07/2024]
Abstract
The advent of liquid biopsies has brought significant changes to the diagnosis and monitoring of non-small cell lung cancer (NSCLC), presenting both promise and challenges. Molecularly targeted drugs, capable of enhancing survival rates, are now available to around a quarter of NSCLC patients. However, to ensure their effectiveness, precision diagnosis is essential. Circulating tumor DNA (ctDNA) analysis as the most advanced liquid biopsy modality to date offers a non-invasive method for tracking genomic changes in NSCLC. The potential of ctDNA is particularly rooted in its ability to furnish comprehensive (epi-)genetic insights into the tumor, thereby aiding personalized treatment strategies. One of the key advantages of ctDNA-based liquid biopsies in NSCLC is their ability to capture tumor heterogeneity. This capability ensures a more precise depiction of the tumor's (epi-)genomic landscape compared to conventional tissue biopsies. Consequently, it facilitates the identification of (epi-)genetic alterations, enabling informed treatment decisions, disease progression monitoring, and early detection of resistance-causing mutations for timely therapeutic interventions. Here we review the current state-of-the-art in ctDNA-based liquid biopsy technologies for NSCLC, exploring their potential to revolutionize clinical practice. Key advancements in ctDNA detection methods, including PCR-based assays, next-generation sequencing (NGS), and digital PCR (dPCR), are discussed, along with their respective strengths and limitations. Additionally, the clinical utility of ctDNA analysis in guiding treatment decisions, monitoring treatment response, detecting minimal residual disease, and identifying emerging resistance mechanisms is examined. Liquid biopsy analysis bears the potential of transforming NSCLC management by enabling non-invasive monitoring of Minimal Residual Disease and providing early indicators for response to targeted treatments including immunotherapy. Furthermore, considerations regarding sample collection, processing, and data interpretation are highlighted as crucial factors influencing the reliability and reproducibility of ctDNA-based assays. Addressing these challenges will be essential for the widespread adoption of ctDNA-based liquid biopsies in routine clinical practice, ultimately paving the way toward personalized medicine and improved outcomes for patients with NSCLC.
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Affiliation(s)
- Chiara Reina
- Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute FPO-IRCCS, Candiolo, Turin, Italy
| | - Berina Šabanović
- Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute FPO-IRCCS, Candiolo, Turin, Italy
| | - Chiara Lazzari
- Department of Medical Oncology, Cancer Institute FPO-IRCCS, Candiolo, Turin, Italy
| | - Vanesa Gregorc
- Department of Medical Oncology, Cancer Institute FPO-IRCCS, Candiolo, Turin, Italy
| | - Christopher Heeschen
- Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute FPO-IRCCS, Candiolo, Turin, Italy;.
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21
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Zhang Y, Li J. Recent advancements in understanding of biological role of homeobox C9 in human cancers. World J Clin Oncol 2024; 15:1168-1176. [PMID: 39351453 PMCID: PMC11438841 DOI: 10.5306/wjco.v15.i9.1168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 07/14/2024] [Accepted: 08/02/2024] [Indexed: 08/29/2024] Open
Abstract
Homeobox (HOX) C9, a member of the HOX family, is an important transcription factor, and it plays a significant role in various biological processes. This family of genes is highly valued for their essential roles in establishing and maintaining the body axis during embryonic development and adult tissues. Further, HOXC9 plays a central role in neuronal differentiation, angiogenesis, and adipose distribution, which are essential for the development of the nervous system, maturation of tissues and organs, and maintenance of energy balance and metabolic health. Recent research has found that abnormal HOXC9 expression is closely associated with the development and progression of various tumor types. The HOXC9 expression level can be an indicator of tumor prognosis. Therefore, elucidating the association between HOXC9 expression and its regulatory mechanisms and tumorigenesis can provide novel insights on the diagnosis and treatment of patients with cancer.
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Affiliation(s)
- Yong Zhang
- Department of Clinical Laboratory, The Affiliated Lianyungang Oriental Hospital of Kangda College of Nanjing Medical University, Lianyungang 222042, Jiangsu Province, China
| | - Jing Li
- Department of Respiratory and Critical Care Medicine, The Affiliated Lianyungang Oriental Hospital of Kangda College of Nanjing Medical University, Lianyungang 222042, Jiangsu Province, China
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22
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Ufimtseva EG, Gileva MS, Kostenko RV, Kozlov VV, Gulyaeva LF. Development of Ex Vivo Analysis for Examining Cell Composition, Immunological Landscape, Tumor and Immune Related Markers in Non-Small-Cell Lung Cancer. Cancers (Basel) 2024; 16:2886. [PMID: 39199657 PMCID: PMC11352364 DOI: 10.3390/cancers16162886] [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: 06/05/2024] [Revised: 07/11/2024] [Accepted: 08/16/2024] [Indexed: 09/01/2024] Open
Abstract
NSCLC is a very aggressive solid tumor, with a poor prognosis due to post-surgical recurrence. Analysis of the specific tumor and immune signatures of NSCLC samples is a critical step in prognostic evaluation and management decisions for patients after surgery. Routine histological assays have some limitations. Therefore, new diagnostic tools with the capability to quickly recognize NSCLC subtypes and correctly identify various markers are needed. We developed a technique for ex vivo isolation of cancer and immune cells from surgical tumor and lung tissue samples of patients with NSCLC (adenocarcinomas and squamous cell carcinomas) and their examination on ex vivo cell preparations and, parallelly, on histological sections after Romanovsky-Giemsa and immunofluorescent/immunochemical staining for cancer-specific and immune-related markers. As a result, PD-L1 expression was detected for some patients only by ex vivo analysis. Immune cell profiling in the tumor microenvironment revealed significant differences in the immunological landscapes between the patients' tumors, with smokers' macrophages with simultaneous expression of pro- and anti-inflammatory cytokines, neutrophils, and eosinophils being the dominant populations. The proposed ex vivo analysis may be used as an additional diagnostic tool for quick examination of cancer and immune cells in whole tumor samples and to avoid false negatives in histological assays.
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Affiliation(s)
- Elena G. Ufimtseva
- Federal Research Center of Fundamental and Translational Medicine, 2 Timakova Street, 630060 Novosibirsk, Russia;
| | - Margarita S. Gileva
- V. Zelman Institute for the Medicine and Psychology, Novosibirsk State University, 1 Pirogova Street, 630090 Novosibirsk, Russia;
| | - Ruslan V. Kostenko
- Novosibirsk Regional Clinical Oncology Dispensary, 2 Plakhotny Street, 630108 Novosibirsk, Russia; (R.V.K.); (V.V.K.)
| | - Vadim V. Kozlov
- Novosibirsk Regional Clinical Oncology Dispensary, 2 Plakhotny Street, 630108 Novosibirsk, Russia; (R.V.K.); (V.V.K.)
- Faculty of General Medicine, Novosibirsk State Medical University, 52 Krasny Prospect, 630091 Novosibirsk, Russia
| | - Lyudmila F. Gulyaeva
- Federal Research Center of Fundamental and Translational Medicine, 2 Timakova Street, 630060 Novosibirsk, Russia;
- V. Zelman Institute for the Medicine and Psychology, Novosibirsk State University, 1 Pirogova Street, 630090 Novosibirsk, Russia;
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23
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Küstermann C, Narbute K, Movčana V, Parfejevs V, Rūmnieks F, Kauķis P, Priedols M, Mikilps-Mikgelbs R, Mihailova M, Andersone S, Dzalbs A, Bajo-Santos C, Krams A, Abols A. iPSC-derived lung and lung cancer organoid model to evaluate cisplatin encapsulated autologous iPSC-derived mesenchymal stromal cell-isolated extracellular vesicles. Stem Cell Res Ther 2024; 15:246. [PMID: 39113093 PMCID: PMC11304910 DOI: 10.1186/s13287-024-03862-6] [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: 12/19/2023] [Accepted: 07/27/2024] [Indexed: 08/10/2024] Open
Abstract
BACKGROUND Lung cancer remains a leading cause of cancer-related mortality globally. Although recent therapeutic advancements have provided targeted treatment approaches, the development of resistance and systemic toxicity remain primary concerns. Extracellular vesicles (EVs), especially those derived from mesenchymal stromal cells (MSC), have gained attention as promising drug delivery systems, offering biocompatibility and minimal immune responses. Recognizing the limitations of conventional 2D cell culture systems in mimicking the tumor microenvironment, this study aims to describe a proof-of-principle approach for using patient-specific organoid models for both lung cancer and normal lung tissue and the feasibility of employing autologous EVs derived from induced pluripotent stem cell (iPSC)-MSC in personalized medicine approaches. METHODS First, we reprogrammed healthy fibroblasts into iPSC. Next, we differentiated patient-derived iPSC into branching lung organoids (BLO) and generated patient-matched lung cancer organoids (LCO) from patient-derived tumor tissue. We show a streamlined process of MSC differentiation from iPSC and EV isolation from iPSC-MSC, encapsulated with 0.07 µg/mL of cytotoxic agent cisplatin and applied to both organoid models. Cytotoxicity of cisplatin and cisplatin-loaded EVs was recorded with LDH and CCK8 tests. RESULTS Fibroblast-derived iPSC showed a normal karyotype, pluripotency staining, and trilineage differentiation. iPSC-derived BLO showed expression of lung markers, like TMPRSS2 and MUC5A while patient-matched LCO showed expression of Napsin and CK5. Next, we compared the effects of iPSC-MSC derived EVs loaded with cisplatin against empty EVs and cisplatin alone in lung cancer organoid and healthy lung organoid models. As expected, we found a cytotoxic effect when LCO were treated with 20 µg/mL cisplatin. Treatment of LCO and BLO with empty EVs resulted in a cytotoxic effect after 24 h. However, EVs loaded with 0.07 µg/mL cisplatin failed to induce any cytotoxic effect in both organoid models. CONCLUSION We report on a proof-of-principle pipeline towards using autologous or allogeneic iPSC-MSC EVs as drug delivery tests for lung cancer in future. However, due to the time and labor-intensive processes, we conclude that this pipeline might not be feasible for personalized approaches at the moment.
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Affiliation(s)
- Caroline Küstermann
- Latvian Biomedical Research and Study Center, Rātsupītes Iela 1, Riga, 1067, Latvia.
| | - Karīna Narbute
- Latvian Biomedical Research and Study Center, Rātsupītes Iela 1, Riga, 1067, Latvia
| | - Valērija Movčana
- Latvian Biomedical Research and Study Center, Rātsupītes Iela 1, Riga, 1067, Latvia
| | - Vadims Parfejevs
- Faculty of Medicine, University of Latvia, Jelgavas Iela 3, Riga, Latvia
| | - Fēlikss Rūmnieks
- Latvian Biomedical Research and Study Center, Rātsupītes Iela 1, Riga, 1067, Latvia
| | - Pauls Kauķis
- Latvian Biomedical Research and Study Center, Rātsupītes Iela 1, Riga, 1067, Latvia
| | - Miks Priedols
- Latvian Biomedical Research and Study Center, Rātsupītes Iela 1, Riga, 1067, Latvia
| | - Rihards Mikilps-Mikgelbs
- Riga East Clinical University Hospital Center of Tuberculosis and Lung Diseases, Upeslejas, Ropažu Novads, Latvia
| | | | | | - Aigars Dzalbs
- IVF Riga Stem Cell Center, Zaļā Iela 1, Rīga, Latvia
| | - Cristina Bajo-Santos
- Latvian Biomedical Research and Study Center, Rātsupītes Iela 1, Riga, 1067, Latvia
| | - Alvils Krams
- Riga East Clinical University Hospital Center of Tuberculosis and Lung Diseases, Upeslejas, Ropažu Novads, Latvia
| | - Arturs Abols
- Latvian Biomedical Research and Study Center, Rātsupītes Iela 1, Riga, 1067, Latvia
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24
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La Salvia A, Meyer ML, Hirsch FR, Kerr KM, Landi L, Tsao MS, Cappuzzo F. Rediscovering immunohistochemistry in lung cancer. Crit Rev Oncol Hematol 2024; 200:104401. [PMID: 38815876 DOI: 10.1016/j.critrevonc.2024.104401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 05/23/2024] [Indexed: 06/01/2024] Open
Abstract
Several observations indicate that protein expression analysis by immunohistochemistry (IHC) remains relevant in individuals with non-small-cell lung cancer (NSCLC) when considering targeted therapy, as an early step in diagnosis and for therapy selection. Since the advent of next-generation sequencing (NGS), the role of IHC in testing for NSCLC biomarkers has been forgotten or ignored. We discuss how protein-level investigations maintain a critical role in defining sensitivity to lung cancer therapies in oncogene- and non-oncogene-addicted cases and in patients eligible for immunotherapy, suggesting that IHC testing should be reconsidered in clinical practice. We also argue how a panel of IHC tests should be considered complementary to NGS and other genomic assays. This is relevant to current clinical diagnostic practice but with potential future roles to optimize the selection of patients for innovative therapies. At the same time, strict validation of antibodies, assays, scoring systems, and intra- and interobserver reproducibility is needed.
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Affiliation(s)
- Anna La Salvia
- National Center for Drug Research and Evaluation, National Institute of Health (ISS), Rome 00161, Italy
| | - May-Lucie Meyer
- Center for Thoracic Oncology/Tisch Cancer Institute and Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Fred R Hirsch
- Center for Thoracic Oncology/Tisch Cancer Institute and Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Keith M Kerr
- Aberdeen University School of Medicine & Aberdeen Royal Infirmary, Aberdeen, UK
| | - Lorenza Landi
- Medical Oncology, Istituto Nazionale Tumori IRCCS "Regina Elena", Rome, Italy
| | - Ming-Sound Tsao
- University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | - Federico Cappuzzo
- Medical Oncology, Istituto Nazionale Tumori IRCCS "Regina Elena", Rome, Italy.
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25
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Ntzifa A, Marras T, Georgoulias V, Lianidou E. Liquid biopsy for the management of NSCLC patients under osimertinib treatment. Crit Rev Clin Lab Sci 2024; 61:347-369. [PMID: 38305080 DOI: 10.1080/10408363.2024.2302116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 10/23/2023] [Accepted: 01/02/2024] [Indexed: 02/03/2024]
Abstract
Therapeutic management of NSCLC patients is quite challenging as they are mainly diagnosed at a late stage of disease, and they present a high heterogeneous molecular profile. Osimertinib changed the paradigm shift in treatment of EGFR mutant NSCLC patients achieving significantly better clinical outcomes. To date, osimertinib is successfully administered not only as first- or second-line treatment, but also as adjuvant treatment while its efficacy is currently investigated during neoadjuvant treatment or in stage III, unresectable EGFR mutant NSCLC patients. However, resistance to osimertinib may occur due to clonal evolution, under the pressure of the targeted therapy. The utilization of liquid biopsy as a minimally invasive tool provides insight into molecular heterogeneity of tumor clonal evolution and potent resistance mechanisms which may help to develop more suitable therapeutic approaches. Longitudinal monitoring of NSCLC patients through ctDNA or CTC analysis could reveal valuable information about clinical outcomes during osimertinib treatment. Therefore, several guidelines suggest that liquid biopsy in addition to tissue biopsy should be considered as a standard of care in the advanced NSCLC setting. This practice could significantly increase the number of NSCLC patients that will eventually benefit from targeted therapies, such as EGFR TKIs.
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Affiliation(s)
- Aliki Ntzifa
- Analysis of Circulating Tumor Cells Lab, Lab of Analytical Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece
| | - Theodoros Marras
- Analysis of Circulating Tumor Cells Lab, Lab of Analytical Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece
| | - Vasilis Georgoulias
- First Department of Medical Oncology, Metropolitan General Hospital of Athens, Cholargos, Greece
| | - Evi Lianidou
- Analysis of Circulating Tumor Cells Lab, Lab of Analytical Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece
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Wang X, Lu Y, Chen S, Zhu Z, Fu Y, Zhang J, He J, Huang L, Luo L, Guo W, Xu Z, Xie Z, Xu X, Zhang Y, Ye F, Ma S. Discovery of a prominent dual-target DDR1/EGFR inhibitor aimed DDR1/EGFR-positive NSCLC. Bioorg Chem 2024; 149:107500. [PMID: 38823310 DOI: 10.1016/j.bioorg.2024.107500] [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: 03/16/2024] [Revised: 05/16/2024] [Accepted: 05/24/2024] [Indexed: 06/03/2024]
Abstract
This study aimed to develop the first dual-target small molecule inhibitor concurrently targeting Discoidin domain receptor 1 (DDR1) and Epidermal growth factor receptor (EGFR), which play a crucial interdependent roles in non-small cell lung cancer (NSCLC), demonstrating a synergistic inhibitory effect. A series of innovative dual-target inhibitors for DDR1 and EGFR were discovered. These compounds were designed and synthesized using structural optimization strategies based on the lead compound BZF02, employing 4,6-pyrimidine diamine as the core scaffold, followed by an investigation of their biological activities. Among these compounds, D06 was selected and showed micromolar enzymatic potencies against DDR1 and EGFR. Subsequently, compound D06 was observed to inhibit NSCLC cell proliferation and invasion. Demonstrating acceptable pharmacokinetic performance, compound D06 exhibited its anti-tumor activity in NSCLC PC-9/GR xenograft models without apparent toxicity or significant weight loss. These collective results showcase the successful synthesis of a potent dual-targeted inhibitor, suggesting the potential therapeutic efficacy of co-targeting DDR1 and EGFR for DDR1/EGFR-positive NSCLC.
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MESH Headings
- Humans
- ErbB Receptors/antagonists & inhibitors
- ErbB Receptors/metabolism
- Discoidin Domain Receptor 1/antagonists & inhibitors
- Discoidin Domain Receptor 1/metabolism
- Lung Neoplasms/drug therapy
- Lung Neoplasms/pathology
- Lung Neoplasms/metabolism
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Carcinoma, Non-Small-Cell Lung/pathology
- Carcinoma, Non-Small-Cell Lung/metabolism
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/chemistry
- Antineoplastic Agents/chemical synthesis
- Cell Proliferation/drug effects
- Structure-Activity Relationship
- Protein Kinase Inhibitors/pharmacology
- Protein Kinase Inhibitors/chemistry
- Protein Kinase Inhibitors/chemical synthesis
- Animals
- Drug Screening Assays, Antitumor
- Molecular Structure
- Dose-Response Relationship, Drug
- Mice
- Drug Discovery
- Mice, Nude
- Neoplasms, Experimental/drug therapy
- Neoplasms, Experimental/pathology
- Neoplasms, Experimental/metabolism
- Cell Line, Tumor
- Mice, Inbred BALB C
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Affiliation(s)
- Xuebao Wang
- School of Public Health, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Ying Lu
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Siyu Chen
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Zhaojingtao Zhu
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yanneng Fu
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Jinxia Zhang
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Jiale He
- School of Public Health, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Lu Huang
- School of Public Health, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Lihong Luo
- School of Public Health, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Weiting Guo
- School of Public Health, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Zhouyang Xu
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Zixin Xie
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Xuemei Xu
- Department of Pharmacy, Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine, Wenzhou, Zhejiang 325035, China.
| | - Yuan Zhang
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
| | - Faqing Ye
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
| | - Shumei Ma
- School of Public Health, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; South Zhejiang Institute of Radiation Medicine and Nuclear Technology, Wenzhou, Zhejiang 325035, China.
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27
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Zhao XC, Ma RF, Liu H, Shan P, Bao J, Zhang H. Grifolin Induces Cell Death of Human Lung Cancer A549 Cell Line via Inhibiting KRAS-Mediated Multiple Signaling Pathways. Chem Biodivers 2024; 21:e202400792. [PMID: 38738487 DOI: 10.1002/cbdv.202400792] [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: 03/27/2024] [Revised: 05/06/2024] [Accepted: 05/13/2024] [Indexed: 05/14/2024]
Abstract
In the current work, grifolin was obtained from the twigs and leaves of Daphne genkwa for the first time and displayed significant growth inhibition against human lung carcinoma A549 cells. Subsequent in vitro antitumor evaluation revealed that grifolin could induce remarkable cell apoptosis and G0/G1 phase arrest, as well as block cell migration and invasion. In addition, grifolin also disrupted cellular energy metabolism by inducing reactive oxygen species, reducing adenosine triphosphate and mitochondrial membrane potential, and damaging DNA synthesis. Further RNA-seq analysis demonstrated that treatment of grifolin on A549 cells led to gene enrichment in MAPK, PI3K/Akt and NF-κB signaling pathways, all of which were inhibited by grifolin according to immunoblotting experiments. Further mechanistical studies disclosed that the expression of a key upstream protein KRAS was also blocked, and the cell death triggered by grifolin could be rescued by a RAS activator ML-099. Moreover, pretreatment of ML-099 on A549 cells could reverse the grifolin-induced downregulation of key proteins in the three aforementioned pathways. These findings indicate that grifolin could induce cell death in A549 cell line by inhibiting KRAS-mediated multiple signaling pathways.
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Affiliation(s)
- Xue-Chun Zhao
- School of Biological Science and Technology, University of Jinan, Jinan, 250022, China E-mail: bio_(H. Zhang) (J. Bao
| | - Ren-Fen Ma
- School of Biological Science and Technology, University of Jinan, Jinan, 250022, China E-mail: bio_(H. Zhang) (J. Bao
| | - Hu Liu
- School of Biological Science and Technology, University of Jinan, Jinan, 250022, China E-mail: bio_(H. Zhang) (J. Bao
| | - Peipei Shan
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, 266021, China
| | - Jie Bao
- School of Biological Science and Technology, University of Jinan, Jinan, 250022, China E-mail: bio_(H. Zhang) (J. Bao
| | - Hua Zhang
- School of Biological Science and Technology, University of Jinan, Jinan, 250022, China E-mail: bio_(H. Zhang) (J. Bao
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Lin X, Yao J, Huang B, Chen T, Xie L, Huang R. Significance of metastatic lymph nodes ratio in overall survival for patients with resected nonsmall cell lung cancer: a retrospective cohort study. Eur J Cancer Prev 2024; 33:376-385. [PMID: 38842873 PMCID: PMC11155287 DOI: 10.1097/cej.0000000000000868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 11/19/2023] [Indexed: 06/07/2024]
Abstract
OBJECTIVE The tumor, node and metastasis stage is widely applied to classify lung cancer and is the foundation of clinical decisions. However, increasing studies have pointed out that this staging system is not precise enough for the N status. In this study, we aim to build a convenient survival prediction model that incorporates the current items of lymph node status. METHODS We performed a retrospective cohort study and collected the data from resectable nonsmall cell lung cancer (NSCLC) (IA-IIIB) patients from the Surveillance, Epidemiology, and End Results database (2006-2015). The x-tile program was applied to calculate the optimal threshold of metastatic lymph node ratio (MLNR). Then, independent prognostic factors were determined by multivariable Cox regression analysis and enrolled to build a nomogram model. The calibration curve as well as the Concordance Index (C-index) were selected to evaluate the nomogram. Finally, patients were grouped based on their specified risk points and divided into three risk levels. The prognostic value of MLNR and examined lymph node numbers (ELNs) were presented in subgroups. RESULTS TOTALLY, 40853 NSCLC patients after surgery were finally enrolled and analyzed. Age, metastatic lymph node ratio, histology type, adjuvant treatment and American Joint Committee on Cancer 8th T stage were deemed as independent prognostic parameters after multivariable Cox regression analysis. A nomogram was built using those variables, and its efficiency in predicting patients' survival was better than the conventional American Joint Committee on Cancer stage system after evaluation. Our new model has a significantly higher concordance Index (C-index) (training set, 0.683 v 0.641, respectively; P < 0.01; testing set, 0.676 v 0.638, respectively; P < 0.05). Similarly, the calibration curve shows the nomogram was in better accordance with the actual observations in both cohorts. Then, after risk stratification, we found that MLNR is more reliable than ELNs in predicting overall survival. CONCLUSION We developed a nomogram model for NSCLC patients after surgery. This novel and useful tool outperforms the widely used tumor, node and metastasis staging system and could benefit clinicians in treatment options and cancer control.
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Affiliation(s)
- Xiaoping Lin
- Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian
| | - Jianfeng Yao
- Department of Reproductive Medicine Centre, Quanzhou Maternity and Child Health Care Hospital
| | - Baoshan Huang
- Department of Pediatrics, The Second Affiliated Hospital, Fujian Medical University
| | - Tebin Chen
- Department of Clinical Laboratory, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, People’s Republic of China
| | - Liutian Xie
- Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian
| | - Rongfu Huang
- Department of Clinical Laboratory, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, People’s Republic of China
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29
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Chauhan R, Gupta A, Dagar G, Sharma S, Sadida HQ, Hashem S, Verghese AM, Tanwar M, Macha MA, Uddin S, Al-Shabeeb Akil AS, Pandita TK, Bhat AA, Singh M. Role of lamins in cellular physiology and cancer. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2024; 143:119-153. [PMID: 39843134 DOI: 10.1016/bs.apcsb.2024.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2025]
Abstract
Lamins, which are crucial type V intermediate filament proteins found in the nuclear lamina, are essential for maintaining the stability and function of the nucleus in higher vertebrates. They are classified into A- and B-types, and their distinct expression patterns contribute to cellular survival, development, and functionality. Lamins emerged during the transition from open to closed mitosis, with their complexity increasing alongside organism evolution. Derived from the LMNA, LMNB1, and LMNB2 genes, lamins undergo alternative splicing to produce seven variants, influencing cellular processes such as stiffness, chromatin condensation, and cell cycle regulation. The lamin network interacts with the cytoskeleton via Linkers of the nucleoskeleton to the cytoskeleton (LINC) complexes, playing a critical role in cellular stability and mechanotransduction. Lamins also regulate active transport into and out of the nucleus, affecting nuclear integrity, positioning, DNA maintenance, and gene expression. Genetic mutations in lamin genes lead to laminopathies, highlighting their functional significance and organizational roles. Changes in lamin subtype composition within the nuclear lamina have significant implications for cancer development, impacting cellular stiffness, mobility, and the Epithelial-to-Mesenchymal Transition (EMT). Lamin A/C, in particular, plays multifaceted roles in cancer biology, influencing progression, metastasis, and therapy response through interactions with various proteins and pathways. Dysregulated lamin expression is commonly observed in cancers, suggesting their potential as diagnostic and prognostic markers. This chapter underscores the pivotal roles of lamins in nuclear architecture and cancer biology, emphasizing their impact on cellular functions and disease pathology. Understanding lamin behavior and regulation mechanisms holds promise for developing novel diagnostic tools and targeted therapies in cancer treatment.
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Affiliation(s)
- Ravi Chauhan
- Department of Medical Oncology (Lab), Dr. B.R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Ashna Gupta
- Department of Medical Oncology (Lab), Dr. B.R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Gunjan Dagar
- Department of Medical Oncology (Lab), Dr. B.R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Shalini Sharma
- Department of Medical Oncology (Lab), Dr. B.R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Hana Q Sadida
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar
| | - Sheema Hashem
- Department of Human Genetics, Sidra Medicine, Doha, Qatar
| | - Ann M Verghese
- Department of Human Genetics, Sidra Medicine, Doha, Qatar
| | - Mukesh Tanwar
- Department of Genetics, Maharishi Dayanand University Rohtak, Haryana, India
| | - Muzafar A Macha
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, Jammu and Kashmir, India
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Ammira S Al-Shabeeb Akil
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar
| | - Tej K Pandita
- Center for Genomics and Precision Medicine, Texas A&M College of Medicine, Houston, TX, United States
| | - Ajaz A Bhat
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar.
| | - Mayank Singh
- Department of Medical Oncology (Lab), Dr. B.R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India.
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30
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Ottaiano A, Grassi F, Sirica R, Genito E, Ciani G, Patanè V, Monti R, Belfiore MP, Urraro F, Santorsola M, Ponsiglione AM, Montella M, Cappabianca S, Reginelli A, Sansone M, Savarese G, Grassi R. Associations between Radiomics and Genomics in Non-Small Cell Lung Cancer Utilizing Computed Tomography and Next-Generation Sequencing: An Exploratory Study. Genes (Basel) 2024; 15:803. [PMID: 38927739 PMCID: PMC11202615 DOI: 10.3390/genes15060803] [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: 05/17/2024] [Revised: 06/14/2024] [Accepted: 06/18/2024] [Indexed: 06/28/2024] Open
Abstract
BACKGROUND Radiomics, an evolving paradigm in medical imaging, involves the quantitative analysis of tumor features and demonstrates promise in predicting treatment responses and outcomes. This study aims to investigate the predictive capacity of radiomics for genetic alterations in non-small cell lung cancer (NSCLC). METHODS This exploratory, observational study integrated radiomic perspectives using computed tomography (CT) and genomic perspectives through next-generation sequencing (NGS) applied to liquid biopsies. Associations between radiomic features and genetic mutations were established using the Area Under the Receiver Operating Characteristic curve (AUC-ROC). Machine learning techniques, including Support Vector Machine (SVM) classification, aim to predict genetic mutations based on radiomic features. The prognostic impact of selected gene variants was assessed using Kaplan-Meier curves and Log-rank tests. RESULTS Sixty-six patients underwent screening, with fifty-seven being comprehensively characterized radiomically and genomically. Predominantly males (68.4%), adenocarcinoma was the prevalent histological type (73.7%). Disease staging is distributed across I/II (38.6%), III (31.6%), and IV (29.8%). Significant correlations were identified with mutations of ROS1 p.Thr145Pro (shape_Sphericity), ROS1 p.Arg167Gln (glszm_ZoneEntropy, firstorder_TotalEnergy), ROS1 p.Asp2213Asn (glszm_GrayLevelVariance, firstorder_RootMeanSquared), and ALK p.Asp1529Glu (glcm_Imc1). Patients with the ROS1 p.Thr145Pro variant demonstrated markedly shorter median survival compared to the wild-type group (9.7 months vs. not reached, p = 0.0143; HR: 5.35; 95% CI: 1.39-20.48). CONCLUSIONS The exploration of the intersection between radiomics and cancer genetics in NSCLC is not only feasible but also holds the potential to improve genetic predictions and enhance prognostic accuracy.
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Affiliation(s)
- Alessandro Ottaiano
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, 80131 Naples, Italy; (A.O.); (M.S.)
| | - Francesca Grassi
- Department of Precision Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (E.G.); (G.C.); (V.P.); (R.M.); (M.P.B.); (F.U.); (S.C.); (A.R.); (R.G.)
| | - Roberto Sirica
- AMES—Centro Polidiagnostico Strumentale, SRL, 80013 Naples, Italy; (R.S.); (G.S.)
| | - Emanuela Genito
- Department of Precision Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (E.G.); (G.C.); (V.P.); (R.M.); (M.P.B.); (F.U.); (S.C.); (A.R.); (R.G.)
| | - Giovanni Ciani
- Department of Precision Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (E.G.); (G.C.); (V.P.); (R.M.); (M.P.B.); (F.U.); (S.C.); (A.R.); (R.G.)
| | - Vittorio Patanè
- Department of Precision Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (E.G.); (G.C.); (V.P.); (R.M.); (M.P.B.); (F.U.); (S.C.); (A.R.); (R.G.)
| | - Riccardo Monti
- Department of Precision Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (E.G.); (G.C.); (V.P.); (R.M.); (M.P.B.); (F.U.); (S.C.); (A.R.); (R.G.)
| | - Maria Paola Belfiore
- Department of Precision Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (E.G.); (G.C.); (V.P.); (R.M.); (M.P.B.); (F.U.); (S.C.); (A.R.); (R.G.)
| | - Fabrizio Urraro
- Department of Precision Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (E.G.); (G.C.); (V.P.); (R.M.); (M.P.B.); (F.U.); (S.C.); (A.R.); (R.G.)
| | - Mariachiara Santorsola
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, 80131 Naples, Italy; (A.O.); (M.S.)
| | - Alfonso Maria Ponsiglione
- Department of Electrical Engineering and Information Technology, University of Naples “Federico II”, 80125 Naples, Italy; (A.M.P.); (M.S.)
| | - Marco Montella
- Pathology Unit, Department of Mental and Physical Health and Preventive Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, 80138 Naples, Italy;
| | - Salvatore Cappabianca
- Department of Precision Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (E.G.); (G.C.); (V.P.); (R.M.); (M.P.B.); (F.U.); (S.C.); (A.R.); (R.G.)
| | - Alfonso Reginelli
- Department of Precision Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (E.G.); (G.C.); (V.P.); (R.M.); (M.P.B.); (F.U.); (S.C.); (A.R.); (R.G.)
| | - Mario Sansone
- Department of Electrical Engineering and Information Technology, University of Naples “Federico II”, 80125 Naples, Italy; (A.M.P.); (M.S.)
| | - Giovanni Savarese
- AMES—Centro Polidiagnostico Strumentale, SRL, 80013 Naples, Italy; (R.S.); (G.S.)
| | - Roberta Grassi
- Department of Precision Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (E.G.); (G.C.); (V.P.); (R.M.); (M.P.B.); (F.U.); (S.C.); (A.R.); (R.G.)
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Rostami F, Tavakol Hamedani Z, Sadoughi A, Mehrabadi M, Kouhkan F. PDL1 targeting by miR-138-5p amplifies anti-tumor immunity and Jurkat cells survival in non-small cell lung cancer. Sci Rep 2024; 14:13542. [PMID: 38866824 PMCID: PMC11169246 DOI: 10.1038/s41598-024-62064-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Accepted: 05/13/2024] [Indexed: 06/14/2024] Open
Abstract
Non-small cell lung cancer (NSCLC) has constituted over 80% of the lung cancer population with a poor prognosis. Over the past decade, immunotherapy has been constructed in the enlargement of immune checkpoint inhibitors as a promising approach for NSCLC treatment. Evading the immune system using the PD-1/PD-L1 axis is an intelligent way for cancers, and T cells cannot respond fully and confront cancer. Recently, the miR-138 was reported as a PD-L1 regulator in NSCLC. However, its inhibitory impact on T-cell exhaustion has not been characterized. The present study aims to impair PD-L1 (B7-H1) expression in Adenocarcinoma cell lines using miR-138-5p and determines how it prevents Jurak cell exhaustion. To gain the purpose, first, 18 highly significant dysregulated miRNAs containing hsa-miR-138 and CD274-mRNA network were detected in NSCLC based on bioinformatics analysis. Moreover, our study revealed a high level of miR-138-5p could make significant changes like PDL1 downregulation, proliferation, and mortality rate in A549/Calu6 cells. We also simulate cancer environmental conditions by culturing Jurak cells and NSCLC cell lines under the influence of stimulator cytokines to show how miR-138-5p survives Jurak cells by targeting PD-L1/PD-1pathway.
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Affiliation(s)
- Fatemeh Rostami
- Stem Cell Technology Research Center (STRC), Iran University of Medical Science (IUMS), P.O. Box: 15856-36473, Tehran, 15856-36473, Iran
| | | | - Azadeh Sadoughi
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Marzieh Mehrabadi
- Stem Cell Technology Research Center (STRC), Iran University of Medical Science (IUMS), P.O. Box: 15856-36473, Tehran, 15856-36473, Iran
| | - Fatemeh Kouhkan
- Stem Cell Technology Research Center (STRC), Iran University of Medical Science (IUMS), P.O. Box: 15856-36473, Tehran, 15856-36473, Iran.
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Feng Y, Zhang T, Liu H. circPDK1 competitively binds miR-4731-5p to mediate GIGYF1 expression and increase paclitaxel sensitivity in non-small cell lung cancer. Discov Oncol 2024; 15:157. [PMID: 38733530 PMCID: PMC11088590 DOI: 10.1007/s12672-024-01003-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 04/30/2024] [Indexed: 05/13/2024] Open
Abstract
OBJECTIVE To investigate the action of circPDK1 in paclitaxel (PTX) resistance in non-small cell lung cancer (NSCLC). METHODS circPDK1, miR-4731-5p, and GIGYF1 levels were determined by RT-qPCR and Western blot. Cell proliferation was detected by CCK-8 and colony formation assay, apoptosis by flow cytometry, invasion by Transwell assay. The targeting relationship between miR-4731-5p and circPDK1 or GIGYF1 was confirmed by dual luciferase reporter gene and RIP assay. A xenograft tumor model was established to determine the role of circPDK1 in PTX resistance. RESULTS circPDK1 was overexpressed in PTX-resistant NSCLC, and depleting circPDK1 hampered proliferation and invasion of PTX-resistant cells, activated apoptosis, and improved PTX sensitivity. circPDK1 bound to miR-4731-5p, and increasing miR-4731-5p expression salvaged the effect of circPDK1 depletion on PTX resistance. miR-4731-5p directly targeted GIGYF1, and upregulating GIGYF1 offset the promoting effect of circPDK1 knockdown on PTX sensitivity. NSCLC tumor growth was inhibited and PTX sensitivity improved when circPDK1 was suppressed. CONCLUSION Depleting circPDK1 promotes PTX sensitivity of NSCLC cells via miR-4731-5p/GIGYF1 axis, thereby inhibiting NSCLC pregnancy.
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Affiliation(s)
- YunYin Feng
- Department of Respiratory, Kaihua County Traditional Chinese Medicine Hospital, No.10 Zhongshan Road, Qinyang Office, Quzhou City, 324000, Zhejiang Province, China.
| | - TaoLong Zhang
- Department of Gastroenterology, Kaihua County Traditional Chinese Medicine Hospital, Quzhou City, 324300, Zhejiang Province, China
| | - Hong Liu
- Department of Respiratory, Kaihua County Traditional Chinese Medicine Hospital, No.10 Zhongshan Road, Qinyang Office, Quzhou City, 324000, Zhejiang Province, China
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Zafra J, Onieva JL, Oliver J, Garrido-Barros M, González-Hernández A, Martínez-Gálvez B, Román A, Ordóñez-Marmolejo R, Pérez-Ruiz E, Benítez JC, Mesas A, Vera A, Chicas-Sett R, Rueda-Domínguez A, Barragán I. Novel Blood Biomarkers for Response Prediction and Monitoring of Stereotactic Ablative Radiotherapy and Immunotherapy in Metastatic Oligoprogressive Lung Cancer. Int J Mol Sci 2024; 25:4533. [PMID: 38674117 PMCID: PMC11050102 DOI: 10.3390/ijms25084533] [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: 03/27/2024] [Revised: 04/12/2024] [Accepted: 04/18/2024] [Indexed: 04/28/2024] Open
Abstract
Up to 80% of patients under immune checkpoint inhibitors (ICI) face resistance. In this context, stereotactic ablative radiotherapy (SABR) can induce an immune or abscopal response. However, its molecular determinants remain unknown. We present early results of a translational study assessing biomarkers of response to combined ICI and SABR (I-SABR) in liquid biopsy from oligoprogressive patients in a prospective observational multicenter study. Cohort A includes metastatic patients in oligoprogression to ICI maintaining the same ICI due to clinical benefit and who receive concomitant SABR. B is a comparative group of oligometastatic patients receiving only SABR. Blood samples are extracted at baseline (T1), after the first (T2) and last (T3) fraction, two months post-SABR (T4) and at further progression (TP). Response is evaluated by iRECIST and defined by the objective response rate (ORR)-complete and partial responses. We assess peripheral blood mononuclear cells (PBMCs), circulating cell-free DNA (cfDNA) and small RNA from extracellular vesicles. Twenty-seven patients could be analyzed (cohort A: n = 19; B: n = 8). Most were males with non-small cell lung cancer and one progressing lesion. With a median follow-up of 6 months, the last ORR was 63% (26% complete and 37% partial response). A decrease in cfDNA from T2 to T3 correlated with a good response. At T2, CD8+PD1+ and CD8+PDL1+ cells were increased in non-responders and responders, respectively. At T2, 27 microRNAs were differentially expressed. These are potential biomarkers of response to I-SABR in oligoprogressive disease.
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Affiliation(s)
- Juan Zafra
- Group of Translational Research in Cancer Immunotherapy (CIMO2), Department of Radiation Oncology, Virgen de la Victoria University Hospital, Institute of Biomedical Research in Malaga (IBIMA), 29010 Málaga, Spain;
- Faculty of Medicine, University of Malaga (UMA), 29071 Málaga, Spain; (J.L.O.); (M.G.-B.); (A.G.-H.)
| | - Juan Luis Onieva
- Faculty of Medicine, University of Malaga (UMA), 29071 Málaga, Spain; (J.L.O.); (M.G.-B.); (A.G.-H.)
- Group of Translational Research in Cancer Immunotherapy (CIMO2), Medical Oncology Intercenter Unit, Regional and Virgen de la Victoria Hospitals, Institute of Biomedical Research in Malaga (IBIMA), 29010 Málaga, Spain; (J.O.); (B.M.-G.); (E.P.-R.); (J.C.B.)
| | - Javier Oliver
- Group of Translational Research in Cancer Immunotherapy (CIMO2), Medical Oncology Intercenter Unit, Regional and Virgen de la Victoria Hospitals, Institute of Biomedical Research in Malaga (IBIMA), 29010 Málaga, Spain; (J.O.); (B.M.-G.); (E.P.-R.); (J.C.B.)
| | - María Garrido-Barros
- Faculty of Medicine, University of Malaga (UMA), 29071 Málaga, Spain; (J.L.O.); (M.G.-B.); (A.G.-H.)
- Group of Translational Research in Cancer Immunotherapy (CIMO2), Medical Oncology Intercenter Unit, Regional and Virgen de la Victoria Hospitals, Institute of Biomedical Research in Malaga (IBIMA), 29010 Málaga, Spain; (J.O.); (B.M.-G.); (E.P.-R.); (J.C.B.)
| | - Andrea González-Hernández
- Faculty of Medicine, University of Malaga (UMA), 29071 Málaga, Spain; (J.L.O.); (M.G.-B.); (A.G.-H.)
- Group of Translational Research in Cancer Immunotherapy (CIMO2), Medical Oncology Intercenter Unit, Regional and Virgen de la Victoria Hospitals, Institute of Biomedical Research in Malaga (IBIMA), 29010 Málaga, Spain; (J.O.); (B.M.-G.); (E.P.-R.); (J.C.B.)
| | - Beatriz Martínez-Gálvez
- Group of Translational Research in Cancer Immunotherapy (CIMO2), Medical Oncology Intercenter Unit, Regional and Virgen de la Victoria Hospitals, Institute of Biomedical Research in Malaga (IBIMA), 29010 Málaga, Spain; (J.O.); (B.M.-G.); (E.P.-R.); (J.C.B.)
| | - Alicia Román
- Department of Radiation Oncology, Virgen de la Victoria University Hospital, Institute of Biomedical Research in Malaga (IBIMA), 29010 Málaga, Spain; (A.R.); (R.O.-M.)
| | - Rafael Ordóñez-Marmolejo
- Department of Radiation Oncology, Virgen de la Victoria University Hospital, Institute of Biomedical Research in Malaga (IBIMA), 29010 Málaga, Spain; (A.R.); (R.O.-M.)
| | - Elisabeth Pérez-Ruiz
- Group of Translational Research in Cancer Immunotherapy (CIMO2), Medical Oncology Intercenter Unit, Regional and Virgen de la Victoria Hospitals, Institute of Biomedical Research in Malaga (IBIMA), 29010 Málaga, Spain; (J.O.); (B.M.-G.); (E.P.-R.); (J.C.B.)
| | - José Carlos Benítez
- Group of Translational Research in Cancer Immunotherapy (CIMO2), Medical Oncology Intercenter Unit, Regional and Virgen de la Victoria Hospitals, Institute of Biomedical Research in Malaga (IBIMA), 29010 Málaga, Spain; (J.O.); (B.M.-G.); (E.P.-R.); (J.C.B.)
| | - Andrés Mesas
- Medical Oncology Intercenter Unit, Regional and Virgen de la Victoria Hospitals, 29010 Málaga, Spain;
| | - Andrés Vera
- Department of Radiation Oncology, Dr Negrín University Hospital, 35010 Las Palmas de Gran Canaria, Spain;
| | - Rodolfo Chicas-Sett
- Department of Radiation Oncology, La Fe University Hospital, 46026 Valencia, Spain;
- Group of Clinical and Translational Cancer Research, Le Fe Health Research Institute, 46026 Valencia, Spain
| | - Antonio Rueda-Domínguez
- Group of Translational Research in Cancer Immunotherapy (CIMO2), Medical Oncology Intercenter Unit, Regional and Virgen de la Victoria Hospitals, Institute of Biomedical Research in Malaga (IBIMA), 29010 Málaga, Spain; (J.O.); (B.M.-G.); (E.P.-R.); (J.C.B.)
| | - Isabel Barragán
- Group of Translational Research in Cancer Immunotherapy (CIMO2), Medical Oncology Intercenter Unit, Regional and Virgen de la Victoria Hospitals, Institute of Biomedical Research in Malaga (IBIMA), 29010 Málaga, Spain; (J.O.); (B.M.-G.); (E.P.-R.); (J.C.B.)
- Group of Pharmacoepigenetics, Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden
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Liu F, Xin M, Feng H, Zhang W, Liao Z, Sheng T, Wen P, Wu Q, Liang T, Shi J, Zhou R, He K, Gu Z, Li H. Cryo-shocked tumor cells deliver CRISPR-Cas9 for lung cancer regression by synthetic lethality. SCIENCE ADVANCES 2024; 10:eadk8264. [PMID: 38552011 PMCID: PMC10980270 DOI: 10.1126/sciadv.adk8264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 02/23/2024] [Indexed: 04/01/2024]
Abstract
Although CRISPR-mediated genome editing holds promise for cancer therapy, inadequate tumor targeting and potential off-target side effects hamper its outcomes. In this study, we present a strategy using cryo-shocked lung tumor cells as a CRISPR-Cas9 delivery system for cyclin-dependent kinase 4 (CDK4) gene editing, which initiates synthetic lethal in KRAS-mutant non-small cell lung cancer (NSCLC). By rapidly liquid nitrogen shocking, we effectively eliminate the pathogenicity of tumor cells while preserving their structure and surface receptor activity. This delivery system enables the loaded CRISPR-Cas9 to efficiently target to lung through the capture in pulmonary capillaries and interactions with endothelial cells. In a NSCLC-bearing mouse model, the drug accumulation is increased nearly fourfold in lung, and intratumoral CDK4 expression is substantially down-regulated compared to CRISPR-Cas9 lipofectamine nanoparticles administration. Furthermore, CRISPR-Cas9 editing-mediated CDK4 ablation triggers synthetic lethal in KRAS-mutant NSCLC and prolongs the survival of mice.
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Affiliation(s)
- Feng Liu
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China
| | - Minhang Xin
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Huiheng Feng
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China
| | - Wentao Zhang
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Ziyan Liao
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China
| | - Tao Sheng
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Ping Wen
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China
| | - Qing Wu
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China
| | - Tingxizi Liang
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China
| | - Jiaqi Shi
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China
| | - Ruyi Zhou
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Kaixin He
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Jinhua Institute of Zhejiang University, Jinhua 321299, China
| | - Zhen Gu
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China
- Jinhua Institute of Zhejiang University, Jinhua 321299, China
- Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China
| | - Hongjun Li
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China
- Jinhua Institute of Zhejiang University, Jinhua 321299, China
- Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Department of Hepatobiliary and Pancreatic Surgery the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
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Thepthanee C, Ei ZZ, Benjakul S, Zou H, Petsri K, Innets B, Chanvorachote P. Shrimp Lipids Inhibit Migration, Epithelial-Mesenchymal Transition, and Cancer Stem Cells via Akt/mTOR/c-Myc Pathway Suppression. Biomedicines 2024; 12:722. [PMID: 38672078 PMCID: PMC11048134 DOI: 10.3390/biomedicines12040722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 03/18/2024] [Accepted: 03/20/2024] [Indexed: 04/28/2024] Open
Abstract
Shrimp is a rich source of bioactive molecules that provide health benefits. However, the high cholesterol content in shrimp oil may pose a risk. We utilized the cholesterol elimination method to obtain cholesterol-free shrimp lipids (CLs) and investigated their anticancer potential, focusing on cancer stem cells (CSCs) and epithelial-to-mesenchymal transition (EMT). Our study focused on CSCs and EMT, as these factors are known to contribute to cancer metastasis. The results showed that treatment with CLs at doses ranging from 0 to 500 µg/mL significantly suppressed the cell migration ability of human lung cancer (H460 and H292) cells, indicating its potential to inhibit cancer metastasis. The CLs at such concentrations did not cause cytotoxicity to normal human keratinocytes. Additionally, CL treatment was found to significantly reduce the levels of Snail, Slug, and Vimentin, which are markers of EMT. Furthermore, we investigated the effect of CLs on CSC-like phenotypes and found that CLs could significantly suppress the formation of a three-dimensional (3D) tumor spheroid in lung cancer cells. Furthermore, CLs induced apoptosis in the CSC-rich population and significantly depleted the levels of CSC markers CD133, CD44, and Sox2. A mechanistic investigation demonstrated that exposing lung cancer cells to CLs downregulated the phosphorylation of Akt and mTOR, as well as c-Myc expression. Based on these findings, we believe that CLs may have beneficial effects on health as they potentially suppress EMT and CSCs, as well as the cancer-potentiating pathway of Akt/mTOR/c-Myc.
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Affiliation(s)
- Chorpaka Thepthanee
- Department of Food Science, School of Food Industry, King Mongkut’s Institute of Technology Ladkrabang, Bangkok 10520, Thailand;
| | - Zin Zin Ei
- Center of Excellence in Cancer Cell and Molecular Biology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand; (Z.Z.E.); (B.I.)
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Soottawat Benjakul
- International Center of Excellence in Seafood Science and Innovation, Faculty of Agro-Industry, Prince of Songkhla University, Songkhla 90110, Thailand;
| | - Hongbin Zou
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China;
| | - Korrakod Petsri
- Department of Pharmacology, Faculty of Medicine, Kasetsart University, Bangkok 10900, Thailand;
| | - Bhurichaya Innets
- Center of Excellence in Cancer Cell and Molecular Biology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand; (Z.Z.E.); (B.I.)
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Pithi Chanvorachote
- Center of Excellence in Cancer Cell and Molecular Biology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand; (Z.Z.E.); (B.I.)
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
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Lotfalizadeh N, Sadr S, Morovati S, Lotfalizadeh M, Hajjafari A, Borji H. A potential cure for tumor-associated immunosuppression by Toxoplasma gondii. Cancer Rep (Hoboken) 2024; 7:e1963. [PMID: 38109851 PMCID: PMC10850000 DOI: 10.1002/cnr2.1963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 11/06/2023] [Accepted: 12/06/2023] [Indexed: 12/20/2023] Open
Abstract
BACKGROUND Recently, immunotherapy has become very hopeful for cancer therapy. Cancer treatment through immunotherapy has excellent specificity and less toxicity than conventional chemoradiotherapy. Pathogens have been used in cancer immunotherapy for a long time. The current study aims to evaluate the possibility of Toxoplasma gondii (T. gondii) as a probable treatment for cancers such as melanoma, breast, ovarian, lung, and pancreatic cancer. RECENT FINDINGS Nonreplicating type I uracil auxotrophic mutants of T. gondii can stimulate immune responses against tumors by reverse immunosuppression at the cellular level. T. gondii can be utilized to research T helper 1 (Th1) cell immunity in intracellular infections. Avirulent T. gondii uracil auxotroph vaccine can change the tumor's immunosuppression and improve the production of type 1 helper cell cytokines, i.e., Interferon-gamma (IFN-γ) and Interleukin-12 (IL-12) and activate tumor-related Cluster of Differentiation 8 (CD8+) T cells to identify and destroy cancer cells. The T. gondii profilin protein, along with T. gondii secreted proteins, have been found to exhibit promising properties in the treatment of various cancers. These proteins are being studied for their potential to inhibit tumor growth and enhance the effectiveness of cancer therapies. Their unique mechanisms of action make them valuable candidates for targeted interventions in ovarian cancer, breast cancer, pancreatic cancer, melanoma, and lung cancer treatments. CONCLUSION In summary, the study underscores the significant potential of harnessing T. gondii, including its diverse array of proteins and antigens, particularly in its avirulent form, as a groundbreaking approach in cancer immunotherapy.
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Affiliation(s)
- Narges Lotfalizadeh
- Department of Pathobiology, Faculty of Veterinary MedicineFerdowsi University of MashhadMashhadIran
| | - Soheil Sadr
- Department of Pathobiology, Faculty of Veterinary MedicineFerdowsi University of MashhadMashhadIran
| | - Solmaz Morovati
- Division of Biotechnology, Department of Pathobiology, School of Veterinary MedicineShiraz UniversityShirazIran
| | - Mohammadhassan Lotfalizadeh
- Board Certificate Oral and Maxillofacial RadiologistNorth Khorasan University of Medical Sciences (NKUMS)BojnurdIran
| | - Ashkan Hajjafari
- Department of Pathobiology, Faculty of Veterinary MedicineIslamic Azad University, Science and Research BranchTehranIran
| | - Hassan Borji
- Department of Pathobiology, Faculty of Veterinary MedicineFerdowsi University of MashhadMashhadIran
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Wang Q, Chen M, Tang X. Luteolin Inhibits Lung Cancer Cell Migration by Negatively Regulating TWIST1 and MMP2 Through Upregulation of miR-106a-5p. Integr Cancer Ther 2024; 23:15347354241247223. [PMID: 38646808 PMCID: PMC11034356 DOI: 10.1177/15347354241247223] [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: 01/04/2024] [Revised: 03/10/2024] [Accepted: 03/29/2024] [Indexed: 04/23/2024] Open
Abstract
BACKGROUND Luteolin, a common dietary flavonoid found in plants, has been shown to have anti-cancer properties. However, its exact mechanisms of action in non-small cell lung cancer (NSCLC) are still not fully understood, particularly its role in regulating broader genomic networks and specific gene targets. In this study, we aimed to elucidate the role of microRNAs (miRNAs) in NSCLC treated with luteolin, using A549 cells as a model system. MATERIALS AND METHODS miRNA profiling was conducted on luteolin-treated A549 cells using Exiqon microarrays, with validation of selected miRNAs by qRT-PCR. Bioinformatic analysis identified the regulatory roles of miRNAs in biological processes and pathways following luteolin treatment. Computational algorithms were employed to identify potential target genes. A549 cells were transfected with miR-106a-5p mimic and inhibitor or their corresponding controls. The expression levels of 2 genes, twist basic helix-loop-helix transcription factor 1 (TWIST1) and matrix metallopeptidase 2 (MMP2), and cell migration were assessed. RESULTS miRNA profiling identified 341 miRNAs, with 18 exhibiting significantly altered expression (P < 0.05). Subsequent qRT-PCR analysis confirmed altered expression of 6 selected miRNAs. KEGG and GO analyses revealed significant alterations in pathways and biological processes crucial for tumor biology. TWIST1 and MMP2, which both contain conserved miR-106a-5p binding sites, exhibited an inverse correlation with the expression levels of miR-106a-5p. Dual-luciferase reporter assays confirmed TWIST1 and MMP2 as direct targets of miR-106a-5p. Luteolin treatment led to a reduction in A549 cell migration, and this reduction was further amplified by the overexpression of miR-106a-5p. CONCLUSION Luteolin inhibits A549 cell migration by modulating the miRNA landscape, shedding light on its mechanisms and laying the foundation for miRNA-based therapeutic approaches for NSCLC.
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Affiliation(s)
- Qiang Wang
- Department of Clinical Laboratory, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310005, People’s Republic of China
| | - Mengyuan Chen
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China
| | - Xiaofang Tang
- Department of Cadre Health Care, Zhejiang Hospital, Hangzhou, People’s Republic of China
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Xu T, Liu X, Liu C, Chen Z, Ma F, Fan D. Development and validation of a nomogram for predicting the overall survival in non-small cell lung cancer patients with liver metastasis. Transl Cancer Res 2023; 12:3061-3073. [PMID: 38130305 PMCID: PMC10731345 DOI: 10.21037/tcr-23-899] [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: 05/25/2023] [Accepted: 09/28/2023] [Indexed: 12/23/2023]
Abstract
Background Among all metastatic lesions in non-small cell lung cancer (NSCLC), liver metastasis (LM) is the most lethal site with a median survival of less than 5 months. Few studies exclusively report on prognostic factors for these unique patients. We aimed to construct and validate a practical model to predict the prognosis of NSCLC patients with LM. Methods Cases of NSCLC with LM diagnosed between 2010 and 2015 were collected from the Surveillance, Epidemiology, and End Results (SEER) database, and were randomly split into training and validation cohort (7:3). The overall survival (OS) was measured from diagnosis until date of death or last follow-up. Cox regression analyses were performed to identify potential predictors of the model. A nomogram incorporating those independent factors was constructed and validated by the concordance index (C-index) and calibration plots. The decision curve analysis (DCA) and a risk stratification system were used to evaluate its clinical value. Results A total of 2,367 cases were selected for analysis and randomized to the training cohort (n=1,677) and the validation cohort (n=690). The patients were mainly male (59.3%), married (83.1%) and White (77.3%). Apart from LM, 54.2%, 26.7%, and 36.7% of patients also present with bone, brain, and lung metastases, respectively. The median follow-up was 4.0 months for all patients and 23 months for alive cases. The median OS was 5 months [interquartile range (IQR), 2-11 months]. Sex, age, race, grade, T stage, bone metastasis, brain metastasis, surgery, and chemotherapy were identified as the independent risk factors of the OS and used to develop the nomogram. The calibration curves exhibited excellent agreement between the predicted and actual survival in both the training and validation set, with a C-index of 0.700 [95% confidence interval (CI): 0.684-0.716] and 0.677 (95% CI: 0.653-0.701), respectively. The DCA and the risk classification system further supported that the prediction model was clinically effective. Conclusions This is the first study to build a prediction model for NSCLC patients with LM. It aids in treatment decisions, focused care, and physician-patient communication. The global prospective data is needed to further improve this model.
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Affiliation(s)
- Tian Xu
- Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xianling Liu
- Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Chaoyuan Liu
- Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zui Chen
- Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Fang Ma
- Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Dan Fan
- Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, China
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Zhang J, Zhang J. Prognostic factors and survival prediction of resected non-small cell lung cancer with ipsilateral pulmonary metastases: a study based on the Surveillance, Epidemiology, and End Results (SEER) database. BMC Pulm Med 2023; 23:413. [PMID: 37899470 PMCID: PMC10614355 DOI: 10.1186/s12890-023-02722-y] [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: 03/20/2023] [Accepted: 10/19/2023] [Indexed: 10/31/2023] Open
Abstract
BACKGROUND Prognostic factors and survival outcomes of non-small cell lung cancer (NSCLC) with Ipsilateral pulmonary metastasis (IPM) are not well-defined. Thus, this study intended to identify the prognostic factors for these patients and construct a predictive nomogram model. METHODS One thousand, seven hundred thirty-two patients with IPM identified between 2000 to 2019 were from the Surveillance, Epidemiology, and End Results (SEER) database. Independent prognostic factors were identified using multivariate Cox regression analyses. Nomograms were constructed to predict the overall survival (OS), C-index, the area under the curve (AUC), and the calibration curve to determine the predictive accuracy and discrimination; the decision curve analysis was used to confirm the clinical utility. RESULTS Patients were randomly divided into training (n = 1213) and validation (n = 519) cohorts. In the training cohort, the multivariable analysis demonstrated that age, sex, primary tumor size, N status, number of regional lymph nodes removed, tumor grade, and chemotherapy were independent prognostic factors for IPM. We constructed a 1-year, 3-year, and 5-year OS prediction nomogram model using independent prognostic factors. The C-index of this model for OS prediction was 0.714 (95% confidence interval [CI], 0.692 to 0.773) in the training cohort and 0.695 (95% CI, 0.660 to 0.730) in the validation cohort. Based on the AUC of the receiver operating characteristic analysis, calibration plots, and decision curve analysis, we concluded that the prognosis model of IPM exhibited excellent performance. Patients with total nomogram points greater than 96 were considered high-risk. CONCLUSION We constructed and internally validated a nomogram to predict 1-year, 3-year, and 5-year OS for NSCLC patients with IPM according to independent prognostic factors. This nomogram demonstrated good calibration, discrimination, clinical utility, and practical decision-making effects for the prognosis of NSCLC patients with IPM.
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Affiliation(s)
- Jiajun Zhang
- Ningxia Medical University, Yinchuan, 750004, People's Republic of China
| | - Jin Zhang
- Department of Respiratory and Critical Care Medicine, General Hospital of Ningxia Medical University, 804 Shengli South Street, Xingqing District, Yinchuan, 750004, China.
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Kannampuzha S, Murali R, Gopalakrishnan AV, Mukherjee AG, Wanjari UR, Namachivayam A, George A, Dey A, Vellingiri B. Novel biomolecules in targeted cancer therapy: a new approach towards precision medicine. Med Oncol 2023; 40:323. [PMID: 37804361 DOI: 10.1007/s12032-023-02168-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 08/18/2023] [Indexed: 10/09/2023]
Abstract
Cancer is a major threat to human life around the globe, and the discovery of novel biomolecules continue to be an urgent therapeutic need that is still unmet. Precision medicine relies on targeted therapeutic strategies. Researchers are better equipped to develop therapies that target proteins as they understand more about the genetic alterations and molecules that cause progression of cancer. There has been a recent diversification of the sorts of targets exploited in treatment. Therapeutic antibody and biotechnology advancements enabled curative treatments to reach previously inaccessible sites. New treatment strategies have been initiated for several undruggable targets. The application of tailored therapy has been proven to have efficient results in controlling cancer progression. Novel biomolecules like SMDCs, ADCs, mABs, and PROTACS has gained vast attention in the recent years. Several studies have shown that using these novel technology helps in reducing the drug dosage as well as to overcome drug resistance in different cancer types. Therefore, it is crucial to fully untangle the mechanism and collect evidence to understand the significance of these novel drug targets and strategies. This review article will be discussing the importance and role of these novel biomolecules in targeted cancer therapies.
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Affiliation(s)
- Sandra Kannampuzha
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Reshma Murali
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India.
| | - Anirban Goutam Mukherjee
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Uddesh Ramesh Wanjari
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Arunraj Namachivayam
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Alex George
- Jubilee Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur, Kerala, India
| | - Abhijit Dey
- Department of Medical Services, MGM Cancer Institute, Chennai, Tamil Nadu, 600029, India
| | - Balachandar Vellingiri
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, Tamil Nadu, 641046, India
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Verplancke KB, Keirns DL, McMahon K, Creech ZA, Truong GT, Silberstein PT, Dahl MB. Association Between Demographic and Socioeconomic Factors and Diagnosis of Advanced Non-small Cell Lung Cancer: An Analysis of the National Cancer Database. Cureus 2023; 15:e44351. [PMID: 37779816 PMCID: PMC10540479 DOI: 10.7759/cureus.44351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/29/2023] [Indexed: 10/03/2023] Open
Abstract
Introduction Lung cancer is a prevalent and potentially lethal cancer. The stage at initial presentation for diagnosis predicts mortality and helps to guide treatment options. Thus, it is critical to determine what factors impact the stage of cancer at diagnosis. This study sought to determine if certain socioeconomic and demographic factors are associated with receiving an early (Stage 0-I) or advanced (Stage IV) diagnosis of non-small cell lung cancer (NSCLC). Methods Using the National Cancer Database (NCDB), 1,149,539 patients were identified as having an NCDB Analytic Stage Group diagnosis of Stage 0-I (early) versus Stage IV (advanced) NSCLC between 2004 and 2018. Patients with early and delayed diagnoses were compared based on specific characteristics including sex, race, ethnicity, number of comorbid conditions, insurance status, median annual income, level of education, geographic location, and reporting facility. Using IBM SPSS Statistics for Windows, Version 28 (Released 2021; IBM Corp., Armonk, New York, United States), the data underwent analysis using binary multivariate logistic regression, chi-square analyses, and one-way ANOVA. Results Factors associated with an advanced diagnosis of NSCLC include being male, Black, Native American, or Hispanic. Compared to patients with at least one comorbid condition, those without comorbid conditions are more likely to present with advanced disease. Patients with private insurance, Medicaid, Medicare, or other government insurance are all less likely to present with advanced-stage cancer than patients without insurance. Compared to patients in the lowest median household income quartile, those in the second and fourth quartiles are diagnosed earlier. Patients living in areas where a higher proportion of residents lack a high school diploma are more likely to present with advanced NSCLC. Additionally, living in the Midwest and Western United States and presenting to Community Cancer programs are associated with advanced disease at initial presentation. Conclusions Factors that were associated with the advanced presentation of NSCLC included being male, Black, Native American, or Hispanic, having a lack of comorbid conditions or insurance, earning a lower median annual income, and living in a zip code where a higher proportion of residents lack a high school diploma. Additionally, residing in the Midwest and Western United States and seeking care at Community Cancer programs were associated with advanced disease at initial presentation. Understanding that certain socioeconomic and demographic factors impact the stage at initial diagnosis of NSCLC can allow for targeted intervention strategies aimed at the most at-risk individuals, areas, and facilities.
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Affiliation(s)
| | | | - Kevin McMahon
- School of Medicine, Creighton University, Omaha, USA
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Padinharayil H, Rai V, George A. Mitochondrial Metabolism in Pancreatic Ductal Adenocarcinoma: From Mechanism-Based Perspectives to Therapy. Cancers (Basel) 2023; 15:1070. [PMID: 36831413 PMCID: PMC9954550 DOI: 10.3390/cancers15041070] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 02/02/2023] [Accepted: 02/06/2023] [Indexed: 02/10/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC), the fourteenth most common malignancy, is a major contributor to cancer-related death with the utmost case fatality rate among all malignancies. Functional mitochondria, regardless of their complex ecosystem relative to normal cells, are essential in PDAC progression. Tumor cells' potential to produce ATP as energy, despite retaining the redox potential optimum, and allocating materials for biosynthetic activities that are crucial for cell growth, survival, and proliferation, are assisted by mitochondria. The polyclonal tumor cells with different metabolic profiles may add to carcinogenesis through inter-metabolic coupling. Cancer cells frequently possess alterations in the mitochondrial genome, although they do not hinder metabolism; alternatively, they change bioenergetics. This can further impart retrograde signaling, educate cell signaling, epigenetic modifications, chromatin structures, and transcription machinery, and ultimately satisfy cancer cellular and nuclear demands. To maximize the tumor microenvironment (TME), tumor cells remodel nearby stromal cells and extracellular matrix. These changes initiate polyclonality, which is crucial for growth, stress response, and metastasis. Here, we evaluate all the intrinsic and extrinsic pathways drawn by mitochondria in carcinogenesis, emphasizing the perspectives of mitochondrial metabolism in PDAC progression and treatment.
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Affiliation(s)
- Hafiza Padinharayil
- Jubilee Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur 680005, Kerala, India
| | - Vikrant Rai
- Department of Translational Research, Western University of Health Sciences, Pomona, CA 91766-1854, USA
| | - Alex George
- Jubilee Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur 680005, Kerala, India
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Li H, Cheng ZJ, Liang Z, Liu M, Liu L, Song Z, Xie C, Liu J, Sun B. Novel nutritional indicator as predictors among subtypes of lung cancer in diagnosis. Front Nutr 2023; 10:1042047. [PMID: 36776604 PMCID: PMC9909296 DOI: 10.3389/fnut.2023.1042047] [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: 09/12/2022] [Accepted: 01/04/2023] [Indexed: 01/27/2023] Open
Abstract
Introduction Lung cancer is a serious global health concern, and its subtypes are closely linked to lifestyle and dietary habits. Recent research has suggested that malnutrition, over-nutrition, electrolytes, and granulocytes have an effect on the development of cancer. This study investigated the impact of combining patient nutritional indicators, electrolytes, and granulocytes as comprehensive predictors for lung cancer treatment outcomes, and applied a machine learning algorithm to predict lung cancer. Methods 6,336 blood samples were collected from lung cancer patients classified as lung squamous cell carcinoma (LUSC), lung adenocarcinoma (LUAD), and small cell lung cancer (SCLC). 2,191 healthy individuals were used as controls to compare the differences in nutritional indicators, electrolytes and granulocytes among different subtypes of lung cancer, respectively. Results Our results demonstrated significant differences between men and women in healthy people and NSCLC, but no significant difference between men and women in SCLC patients. The relationship between indicators is basically that the range of indicators for cancer patients is wider, including healthy population indicators. In the process of predicting lung cancer through nutritional indicators by machine learning, the AUC of the random forest model was as high as 93.5%, with a sensitivity of 75.9% and specificity of 96.5%. Discussion This study supports the feasibility and accuracy of nutritional indicators in predicting lung cancer through the random forest model. The successful implementation of this novel prediction method could guide clinicians in providing both effective diagnostics and treatment of lung cancers.
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Affiliation(s)
- Haiyang Li
- Department of Clinical Laboratory, National Clinical Research Center of Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
- Department of Allergy and Clinical Immunology, National Clinical Research Center of Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
- Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Zhangkai J. Cheng
- Department of Clinical Laboratory, National Clinical Research Center of Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
- Department of Allergy and Clinical Immunology, National Clinical Research Center of Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Zhiman Liang
- Department of Clinical Laboratory, National Clinical Research Center of Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
- Department of Allergy and Clinical Immunology, National Clinical Research Center of Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Mingtao Liu
- Department of Clinical Laboratory, National Clinical Research Center of Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
- Department of Allergy and Clinical Immunology, National Clinical Research Center of Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Li Liu
- Department of Clinical Laboratory, National Clinical Research Center of Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
- Department of Allergy and Clinical Immunology, National Clinical Research Center of Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Zhenfeng Song
- Department of Clinical Laboratory, National Clinical Research Center of Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
- Department of Allergy and Clinical Immunology, National Clinical Research Center of Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Chuanbo Xie
- Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Junling Liu
- Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Baoqing Sun
- Department of Clinical Laboratory, National Clinical Research Center of Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
- Department of Allergy and Clinical Immunology, National Clinical Research Center of Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
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Padinharayil H, Alappat RR, Joy LM, Anilkumar KV, Wilson CM, George A, Valsala Gopalakrishnan A, Madhyastha H, Ramesh T, Sathiyamoorthi E, Lee J, Ganesan R. Advances in the Lung Cancer Immunotherapy Approaches. Vaccines (Basel) 2022; 10:1963. [PMID: 36423060 PMCID: PMC9693102 DOI: 10.3390/vaccines10111963] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 11/13/2022] [Accepted: 11/17/2022] [Indexed: 09/19/2023] Open
Abstract
Despite the progress in the comprehension of LC progression, risk, immunologic control, and treatment choices, it is still the primary cause of cancer-related death. LC cells possess a very low and heterogeneous antigenicity, which allows them to passively evade the anticancer defense of the immune system by educating cytotoxic lymphocytes (CTLs), tumor-infiltrating lymphocytes (TILs), regulatory T cells (Treg), immune checkpoint inhibitors (ICIs), and myeloid-derived suppressor cells (MDSCs). Though ICIs are an important candidate in first-line therapy, consolidation therapy, adjuvant therapy, and other combination therapies involving traditional therapies, the need for new predictive immunotherapy biomarkers remains. Furthermore, ICI-induced resistance after an initial response makes it vital to seek and exploit new targets to benefit greatly from immunotherapy. As ICIs, tumor mutation burden (TMB), and microsatellite instability (MSI) are not ideal LC predictive markers, a multi-parameter analysis of the immune system considering tumor, stroma, and beyond can be the future-oriented predictive marker. The optimal patient selection with a proper adjuvant agent in immunotherapy approaches needs to be still revised. Here, we summarize advances in LC immunotherapy approaches with their clinical and preclinical trials considering cancer models and vaccines and the potential of employing immunology to predict immunotherapy effectiveness in cancer patients and address the viewpoints on future directions. We conclude that the field of lung cancer therapeutics can benefit from the use of combination strategies but with comprehension of their limitations and improvements.
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Affiliation(s)
- Hafiza Padinharayil
- Jubilee Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur 680005, Kerala, India
| | - Reema Rose Alappat
- Jubilee Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur 680005, Kerala, India
| | - Liji Maria Joy
- Jubilee Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur 680005, Kerala, India
| | - Kavya V. Anilkumar
- Jubilee Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur 680005, Kerala, India
| | - Cornelia M. Wilson
- Life Sciences Industry Liaison Lab, School of Psychology and Life Sciences, Canterbury Christ Church University, Sandwich CT13 9ND, UK
| | - Alex George
- Jubilee Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur 680005, Kerala, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India
| | - Harishkumar Madhyastha
- Department of Cardiovascular Physiology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan
| | - Thiyagarajan Ramesh
- Department of Basic Medical Sciences, College of Medicine, Prince Sattam bin Abdulaziz University, P.O. Box 173, Al-Kharj 11942, Saudi Arabia
| | | | - Jintae Lee
- School of Chemical Engineering, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Raja Ganesan
- Institute for Liver and Digestive Diseases, College of Medicine, Hallym University, Chuncheon 24253, Republic of Korea
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Nanomedicine for targeting the lung cancer cells by interpreting the signaling pathways. J Drug Deliv Sci Technol 2022. [DOI: 10.1016/j.jddst.2022.103865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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