Cancer Therapeutics Insights YM-155 Potentiates the Effect of ABT-737 in Malignant HumanGliomaCells viaSurvivin andMcl-1Downregulation in an EGFR-Dependent Context
نویسندگان
چکیده
Antiapoptotic proteins are commonly overexpressed in gliomas, contributing to therapeutic resistance. We recently reported that clinically achievable concentrations of the Bcl-2/Bcl-xL inhibitor ABT-737 failed to induce apoptosis in glioma cells, with persistent expression of survivin andMcl-1. To address the role of these mediators in glioma apoptosis resistance, we analyzed the effects of YM-155, a survivin suppressant, on survival on a panel of glioma cell lines. YM-155 inhibited cell growth anddownregulated survivin andMcl-1 in adoseandcell line–dependentmanner.WhileU373, LN18, LNZ428, T98G,LN229, andLNZ308 cells exhibited an IC50 of 10 to 75 nmol/L, A172 cells were resistant (IC50 250 nmol/L). No correlation was found between sensitivity to YM-155 and baseline expression of survivin or cIAP-1/cIAP-2/XIAP. However, strong correlation was observed between EGF receptor (EGFR) activation levels and YM-155 response, which was confirmed using EGFR-transduced versus wild-type cells. Because we postulated that decreasing Mcl-1 expression may enhance glioma sensitivity to ABT-737, we examined whether cotreatment with YM-155 promoted ABT-737 efficacy. YM-155 synergistically enhanced ABT-737–induced cytotoxicity and caspasedependent apoptosis. Downregulation of Mcl-1 using short hairpin RNA also enhanced ABT-737–inducing killing, confirming an important role forMcl-1 inmediating synergism betweenABT-737 andYM-155. Aswith YM-155 alone, sensitivity to YM-155 and ABT-737 inversely correlated with EGFR activation status. However, sensitivity could be restored in highly resistant U87-EGFRvIII cells by inhibition of EGFR or its downstream pathways, highlighting the impact of EGFR signaling on Mcl-1 expression and the relevance of combined targeted therapies to overcome the multiple resistance mechanisms of these aggressive tumors. Mol Cancer Ther; 12(3); 326–38. 2013 AACR.
منابع مشابه
YM-155 potentiates the effect of ABT-737 in malignant human glioma cells via survivin and Mcl-1 downregulation in an EGFR-dependent context.
Antiapoptotic proteins are commonly overexpressed in gliomas, contributing to therapeutic resistance. We recently reported that clinically achievable concentrations of the Bcl-2/Bcl-xL inhibitor ABT-737 failed to induce apoptosis in glioma cells, with persistent expression of survivin and Mcl-1. To address the role of these mediators in glioma apoptosis resistance, we analyzed the effects of YM...
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