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.


CONCLUSIONS
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.
Fujie
Yujiro
Y
Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita-City, Osaka 565-0871, Japan.
Yamamoto
Hirofumi
H
Ngan
Chew Yee
CY
Takagi
Akimitsu
A
Hayashi
Taro
T
Suzuki
Rei
R
Ezumi
Koji
K
Takemasa
Ichiro
I
Ikeda
Masataka
M
Sekimoto
Mitsugu
M
Matsuura
Nariaki
N
Monden
Morito
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008938:Mitosis / Q000187:drug effects; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D017239:Paclitaxel / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D051028:bcl-2-Associated X Protein
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D015853:Cysteine Proteinase Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D009944:Organoplatinum Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D000077150:Oxaliplatin; D020169:Caspases; D017239:Paclitaxel