Oxaliplatin, a Potent Inhibitor of Survivin, Enhances Paclitaxel-induced Apoptosis and Mitotic Catastrophe in Colon Cancer Cells

• Published in: Japanese journal of clinical oncology 2005-08, Vol.35 (8), p.453-463
• Main Authors: Fujie, Yujiro, Yamamoto, Hirofumi, Ngan, Chew Yee, Takagi, Akimitsu, Hayashi, Taro, Suzuki, Rei, Ezumi, Koji, Takemasa, Ichiro, Ikeda, Masataka, Sekimoto, Mitsugu, Matsuura, Nariaki, Monden, Morito
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; apoptosis; Apoptosis - drug effects; bcl-2-Associated X Protein; Caspases - metabolism; Cell Cycle - drug effects; Cell Line, Tumor; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Cysteine Proteinase Inhibitors - pharmacology; Drug Synergism; Humans; Inhibitor of Apoptosis Proteins; Microtubule-Associated Proteins - antagonists & inhibitors; Microtubule-Associated Proteins - biosynthesis; Mitosis - drug effects; mitotic catastrophe; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - biosynthesis; Organoplatinum Compounds - pharmacology; oxaliplatin; Paclitaxel - pharmacology; Proto-Oncogene Proteins c-bcl-2 - biosynthesis; survivin; taxol; Tumor Suppressor Protein p53 - genetics
• ISSN: 0368-2811; 1465-3621
• DOI: 10.1093/jjco/hyi130

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 IC50 induced apoptosis and cell cycle arrest at G2–M phase. Western blot analyses indicated that oxaliplatin decreased mitosis-commencing protein cdc2 and anti-apoptotic proteins, phospho-Bcl2 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.