Oxaliplatin, a potent inhibitor of survivin, enhances paclitaxel-induced apoptosis and mitotic catastrophe in colon cancer cells.

BACKGROUND Clinical studies have demonstrated that oxaliplatin, a novel platinum derivative, is a potent chemotherapeutic agent, especially when combined with other reagents. The aim of the present study was to explore the mechanism of such action. METHODS Using colon cancer cell lines, we examined changes in cell cycle, apoptosis and mitotic catastrophe induced by oxaliplatin and/or paclitaxel. RESULTS Oxaliplatin at its IC(50) induced apoptosis and cell cycle arrest at G(2)-M phase. Western blot analyses indicated that oxaliplatin decreased mitosis-commencing protein cdc2 and anti-apoptotic proteins, phospho-Bcl(2) and Bcl-xl in the three colon cancer cells tested. Since cdc2 stabilizes survivin, a putative IAP (inhibitor of apoptosis) family member, through phosphorylation of Thr34, we examined the level of survivin and found a marked decrease due to oxaliplatin. This finding is of particular interest because survivin is a promising molecular target against various human cancers and a key molecule involved in both apoptosis and mitotic catastrophe. When used in combination with paclitaxel (taxol), a putative apoptosis-inducing reagent, the isobologram indicated that the taxol-oxaliplatin sequence or taxol plus oxaliplatin had synergic or additive effects, while the oxaliplatin-taxol sequence resulted in a prominent antagonism. The taxol-oxaliplatin sequence caused marked growth inhibition of DLD1 and SW480 cells, possibly due to upregulation of apoptotic and non-apoptotic pathways, respectively. Morphological surveys indicated that the non-apoptotic process could be mitotic catastrophe. CONCLUSION Our results suggest that oxaliplatin that potently inhibited survivin may exert outstanding cytotoxic effects when combined with certain chemoreagents through enhancement of apoptosis and mitotic catastrophe.