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.

In glioblastomas, apoptosis inhibitor proteins (IAPs) are involved in apoptotic and non-apoptotic processes. Here we used GDC-0152, a small molecule IAP inhibitor, to explore how IAPs participate in glioblastoma stem-like cell maintenance and fate under both hypoxic and normoxic environments. In hypoxia, IAPs inhibition triggered stem-like cells apoptosis and decreased proliferation in four human glioblastoma cell lines, whereas in normoxia it induced a loss of stemness and differentiation. In addition, we characterized a 3D glioblastoma spheroid model. By using MALDI images we validated that GDC-0152 penetrates in the entire sphere. TOF-SIMS analyses revealed an oxygen gradient correlated with spatial cellular heterogeneity with proliferative and apoptotic cells located close to the hypoxic core and GFAP ⁺ cells at the periphery. Notably, Serine-Threonine Kinases activation analysis revealed that oxygen level affects signaling pathways activated by GDC-0152. In hypoxia, IAPs inhibition activated ATR whereas in normoxia it activated NF-κB. Our data brings new mechanistic insights revealing the dual role of IAPs inhibitors like GDC-0152 that are relevant to their therapeutic application in tumors like glioblastomas.