{"title":"Cancer-Associated Fibroblasts Enhance Oxaliplatin Resistance in Colorectal Cancer Cells via Paracrine IL-6: An In Vitro Study.","authors":"Jiahui Wang, Yanxin Lu, Zhiyong Wang, Pei Wei","doi":"10.5812/ijpr-160886","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) often develops resistance to oxaliplatin (L-OHP), a key chemotherapeutic agent. Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are implicated in chemoresistance, but their role in L-OHP resistance via interleukin-6 (IL-6) secretion remains unclear.</p><p><strong>Objectives: </strong>The presnt study investigated how CAFs contribute to L-OHP resistance in CRC, focusing on IL-6 secretion and its impact on cancer cell survival.</p><p><strong>Methods: </strong>NIH3T3 fibroblasts were co-cultured with murine (CT26) or human (DLD1) colon cancer cells and treated with L-OHP. The supernatant IL-6 levels were measured by enzyme-linked immunosorbent assay (ELISA). Indirect co-culture using Transwell chambers was employed to separate CAF and tumor cell effects. Conditioned media (CM) from both cell types were collected and analyzed for IL-6. Cytotoxicity assays were conducted to assess the survival of L-OHP-treated CT26 cells in the presence of CAF-derived CM, with or without an IL-6-neutralizing antibody.</p><p><strong>Results: </strong>Co-culture significantly increased IL-6 secretion, which was further amplified by L-OHP. The IL-6 levels in CAF-derived CM were approximately 3.5-fold higher than in tumor cell-derived CM. The CAF-derived CM improved the survival of L-OHP-treated CT26 cells, an effect reversed by IL-6-neutralizing antibodies. Furthermore, adding exogenous IL-6 to tumor cell-derived CM also enhanced survival. Similar IL-6 upregulation in cisplatin-treated CAFs suggests a broader role in platinum-based resistance.</p><p><strong>Conclusions: </strong>The CAFs promote L-OHP resistance in CRC through IL-6 secretion, enhancing cancer cell survival. Therefore, targeting CAFs and IL-6 signaling may help overcome chemoresistance in CRC.</p>","PeriodicalId":14595,"journal":{"name":"Iranian Journal of Pharmaceutical Research","volume":"24 1","pages":"e160886"},"PeriodicalIF":1.8000,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12296695/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Iranian Journal of Pharmaceutical Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.5812/ijpr-160886","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q3","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Colorectal cancer (CRC) often develops resistance to oxaliplatin (L-OHP), a key chemotherapeutic agent. Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are implicated in chemoresistance, but their role in L-OHP resistance via interleukin-6 (IL-6) secretion remains unclear.
Objectives: The presnt study investigated how CAFs contribute to L-OHP resistance in CRC, focusing on IL-6 secretion and its impact on cancer cell survival.
Methods: NIH3T3 fibroblasts were co-cultured with murine (CT26) or human (DLD1) colon cancer cells and treated with L-OHP. The supernatant IL-6 levels were measured by enzyme-linked immunosorbent assay (ELISA). Indirect co-culture using Transwell chambers was employed to separate CAF and tumor cell effects. Conditioned media (CM) from both cell types were collected and analyzed for IL-6. Cytotoxicity assays were conducted to assess the survival of L-OHP-treated CT26 cells in the presence of CAF-derived CM, with or without an IL-6-neutralizing antibody.
Results: Co-culture significantly increased IL-6 secretion, which was further amplified by L-OHP. The IL-6 levels in CAF-derived CM were approximately 3.5-fold higher than in tumor cell-derived CM. The CAF-derived CM improved the survival of L-OHP-treated CT26 cells, an effect reversed by IL-6-neutralizing antibodies. Furthermore, adding exogenous IL-6 to tumor cell-derived CM also enhanced survival. Similar IL-6 upregulation in cisplatin-treated CAFs suggests a broader role in platinum-based resistance.
Conclusions: The CAFs promote L-OHP resistance in CRC through IL-6 secretion, enhancing cancer cell survival. Therefore, targeting CAFs and IL-6 signaling may help overcome chemoresistance in CRC.
期刊介绍：
The Iranian Journal of Pharmaceutical Research (IJPR) is a peer-reviewed multi-disciplinary pharmaceutical publication, scheduled to appear quarterly and serve as a means for scientific information exchange in the international pharmaceutical forum. Specific scientific topics of interest to the journal include, but are not limited to: pharmaceutics, industrial pharmacy, pharmacognosy, toxicology, medicinal chemistry, novel analytical methods for drug characterization, computational and modeling approaches to drug design, bio-medical experience, clinical investigation, rational drug prescribing, pharmacoeconomics, biotechnology, nanotechnology, biopharmaceutics and physical pharmacy.
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