Picropodophyllin, an IGF‑1 receptor inhibitor, enhances oxaliplatin efficacy in chemoresistant colorectal cancer HCT116 cells by reducing metastatic potential.

Abstract

The insulin-like growth factor receptor (IGF-1R) axis drives cellular growth, survival and chemoresistance in colorectal cancer (CRC) by promoting proliferative signaling, anti-apoptotic effects and epithelial-mesenchymal transition (EMT). Targeting the IGF-1R pathway is therefore a promising strategy, not only for overcoming drug resistance, but also for reducing migration and metastatic behavior related to EMT. The present study aimed to evaluate the potential of picropodophyllin (PPP), a selective IGF-1R inhibitor, to enhance the effects of oxaliplatin (OX) in HCT116 and OX-resistant HCT116-R cells. Cell viability was evaluated using a resazurin-based assay following 48-h combination treatment with OX at its IC₅₀ concentrations (HCT116 cells, 53 µM and HCT116-R cells, 324 µM) and PPP (1 µM). Migration was assessed using wound healing assays, with images captured and analyzed at 0 and 48 h. Additionally, immunofluorescence staining was performed to assess E-cadherin and vimentin expression, evaluating epithelial and mesenchymal characteristics. In HCT116-R cells, the combination of OX (53 µM) and PPP significantly reduced cell viability by 0.65-fold compared with OX alone (P=0.0286). Wound healing assays demonstrated that combining PPP with OX (53 and 324 µM) significantly decreased migration, with 0.34-fold and 0.22-fold reductions, respectively (P<0.05). Immunofluorescence staining revealed that this combination also significantly increased E-cadherin expression, by 1.37- and 1.63-fold, respectively (P<0.05), indicating the role of PPP in enhancing epithelial characteristics and reducing EMT-related drug resistance. These findings highlight the potential for combining PPP with OX to enhance the cytotoxic and anti-metastatic effects of OX in chemo-resistant CRC cells, thus offering a promising strategy for overcoming drug resistance and improving patient outcomes in CRC treatment.