Gemcitabine: An Alternative Treatment for Oxaliplatin-Resistant Colorectal Cancer

SIMPLE SUMMARY: Colorectal cancer is the third most common cancer worldwide. The treatment of the advanced stages is based on poly-chemotherapies, including oxaliplatin. However, the development of resistance to chemotherapy is observed in 50% of cases, leading to treatment failures. A better understanding of the resistance mechanisms is therefore crucial to improve treatment efficiency and patient survival. In our previous work, showed that ROS production and the p38 MAPK pathway were strongly involved in resistance to oxaliplatin. In this study, we tested several chemotherapies and observed that only gemcitabine efficiently treated oxaliplatin-resistant cancer cells. Indeed, gemcitabine was able to induce apoptosis by inhibiting both the Akt and p38 MAPK pathways. Taken together, our results show that gemcitabine could be an interesting therapeutic option for patients with oxaliplatin-resistant tumors. ABSTRACT: Resistance to treatments is one of the leading causes of cancer therapy failure. Oxaliplatin is a standard chemotherapy used to treat metastatic colorectal cancer. However, its efficacy is greatly reduced by the development of resistances. In a previous study, we deciphered the mechanisms leading to oxaliplatin resistance and highlighted the roles played by ROS production and the p38 MAPK pathway in this phenomenon. In this report, we studied the effects of different chemotherapy molecules on our oxaliplatin-resistant cells to identify alternative treatments. Among all the studied molecules, gemcitabine was the only one to present a major cytotoxic effect on oxaliplatin-resistant cancer cells both in vivo and in vitro. However, the combination of oxaliplatin and gemcitabine did not present any major interest. Indeed, the study of combination efficiency using Chou and Talalay’s method showed no synergy between oxaliplatin and gemcitabine. Using PamGene technology to decipher gemcitabine’s effects on oxaliplatin-resistant cells, we were able to show that gemcitabine counteracts chemoresistance by strongly inhibiting the Akt and src/p38 MAPK pathways, leading to apoptosis induction and cell death. In view of these results, gemcitabine could be an interesting alternative therapy for patients with colorectal cancer not responding to oxaliplatin-based protocols such as FOLFOX.