Inhibition of heat shock proteins enhances arsenic trioxide-induced mitotic cell death

A42 Arsenic trioxide (ATO) has recently emerged as a promising therapeutic agent against leukemia through induction of apoptosis. However, evidence to support the therapeutic applications of ATO for treatment of other types of cancers remains to be inadequate. Heat shock proteins (HSPs) counteract with apoptotic protein to restrain cancer cells from apoptosis. In addition, HSPs are known to be cytoprotective against ATO cytotoxicity. In this study, we investigated whether and how 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17-DMAG, an inhibitor of HSP90 ATPase) and KNK437 (an inhibitor of HSP70 synthesis) could enhance ATO-induced apoptosis to cancer cell lines. Our results showed that co-treatment of 17-DMAG or KNK437 with ATO significantly increased ATO-induced cell death in HeLa-S3 cells. Furthermore, 17-DMAG or KNK437 considerably enhanced ATO-induced mitotic arrest, spindle multipolarity, and subsequent mitotic apoptosis. Since only pretreatment or cotreatment of 17-DMAG or KNK437 with ATO significantly enhanced ATO-induced mitotic arrest indicating that the effects of 17-DMAG or KNK437 were schedule-dependent. These results indicated that inhibition of HSPs can enhance ATO-induced cytotoxicity in HeLa-S3 cells probably through augmentation of ATO-induced mitotic derangement.