Modeling ovarian cancer chemoresistance: establishment of murine ID8 sublines and elucidation of adaptive mechanisms

Introduction Acquired resistance to platinum-taxane chemotherapy is a major cause of treatment failure in ovarian cancer (OC). In vitro cell models are indispensable tools for investigating chemoresistance mechanisms, and the establishment of new resistant cell models contributes to a more comprehensive understanding of these mechanisms. Currently, syngeneic mouse cell models remain scarce. Methods Paclitaxel- and carboplatin-resistant sublines (ID8-T and ID8-C) were established by intermittent drug exposure from parental ID8 cells. Cellular morphology was assessed by Giemsa staining. Cell viability was determined using CCK-8 and colony formation assays. Flow cytometry was employed to analyze cell cycle distribution and apoptosis rate. Intracellular drug concentration was quantified by high-performance liquid chromatography (HPLC). Reactive oxygen species (ROS) levels were detected with a fluorescent probe, and protein expression profiles were analyzed by Western blotting. Results Both ID8-T and ID8-C exhibited significant resistance to their inducing agents, with resistance indices of 4.54 and 2.21, respectively, and demonstrated cross-resistance phenotype. They showed enhanced clonogenic survival and attenuated drug-induced cell cycle arrest and apoptosis. Mechanistically, resistant cells exhibited reduced intracellular drug accumulation, maintained lower ROS levels, and displayed altered expression of key regulatory proteins. These included sustained pro-survival signals (MCM2, STAT3, 4E-BP1), impaired apoptotic execution (reduced cleaved caspase-3/PARP/LaminA/C), upregulation of the drug efflux pump ABCB1, and dysregulated mitochondrial fission machinery (downregulated MFF). Conclusion We have established and characterized two novel murine OC chemoresistance models. The resistant phenotypes of ID8-T and ID8-C sublines are associated with a multifaceted adaptive signature involving enhanced drug efflux, evasion of cell cycle arrest and apoptosis, reduced ROS levels, and altered expression of proteins related to mitochondrial fission. These well-characterized syngeneic models provide valuable tools for future mechanistic and therapeutic studies aimed at overcoming chemotherapy resistance in OC.