Japanese Journal of Clinical Oncology Advance Access originally published online on July 15, 2005
Japanese Journal of Clinical Oncology 2005 35(8):453-463; doi:10.1093/jjco/hyi130
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© 2005 Foundation for Promotion of Cancer Research
Oxaliplatin, a Potent Inhibitor of Survivin, Enhances Paclitaxel-induced Apoptosis and Mitotic Catastrophe in Colon Cancer Cells
1 Department of Surgery and Clinical Oncology, Graduate School of Medicine, 3 Department of Pathology, School of Allied Health Science, Faculty of Medicine, Osaka University, Suita, Osaka and 2 Yakult Central Institute for Microbiological Research, Kunitachi, Tokyo, Japan
For reprints and all correspondence: Hirofumi Yamamoto, Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita-City, Osaka 565-0871, Japan. E-mail: kobunyam{at}surg2.med.osaka-u.ac.jp
Received April 2, 2005; accepted June 19, 2005
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.
Key Words: oxaliplatin • taxol • survivin • apoptosis • mitotic catastrophe
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