Heat shock protein inhibitors, 17-DMAG and KNK437, enhance arsenic trioxide-induced mitotic apoptosis.
Arsenic trioxide (ATO) has recently emerged as a promising therapeutic agent in leukemia because of its ability to induce apoptosis. However, there is no sufficient evidence to support its therapeutic use for other types of cancers. In this study, we investigated if, and how, 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17-DMAG), an antagonist of heat shock protein 90 (HSP90), and KNK437, a HSP synthesis inhibitor, potentiated the cytotoxic effect of ATO. Our results showed that cotreatment with ATO and either 17-DMAG or KNK437 significantly increased ATO-induced cell death and apoptosis. siRNA-mediated attenuation of the expression of the inducible isoform of HSP70 (HSP70i) or HSP90alpha/beta also enhanced ATO-induced apoptosis. In addition, cotreatment with ATO and 17-DMAG or KNK437 significantly increased ATO-induced mitotic arrest and ATO-induced BUBR1 phosphorylation and PDS1 accumulation. Cotreatment also significantly increased the percentage of mitotic cells with abnormal mitotic spindles and promoted metaphase arrest as compared to ATO treatment alone. These results indicated that 17-DMAG or KNK437 may enhance ATO cytotoxicity by potentiating mitotic arrest and mitotic apoptosis possibly through increased activation of the spindle checkpoint.
Wu
Yi-Chen
YC
Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan, ROC.
Yen
Wen-Yen
WY
Lee
Te-Chang
TC
Yih
Ling-Huei
LH
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D000077237:Arsenic Trioxide; D001152:Arsenicals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D016227:Benzoquinones / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008938:Mitosis / Q000187:drug effects* / Q000502:physiology; D010087:Oxides / Q000633:toxicity*; D011760:Pyrrolidinones / Q000494:pharmacology*
D001152:Arsenicals; D001559:Benzhydryl Compounds; D016227:Benzoquinones; D004785:Environmental Pollutants; D006360:Heat-Shock Proteins; C410027:KNK 437; D047029:Lactams, Macrocyclic; D010087:Oxides; D011760:Pyrrolidinones; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D000077237:Arsenic Trioxide