YM-155 potentiates the effect of ABT-737 in malignant human glioma cells via survivin and Mcl-1 downregulation in an EGFR-dependent context

Document Type

Article

Abstract

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-155, a survivin suppressant, on survival on a panel of glioma cell lines. YM-155 inhibited cell growth and downregulated survivin and Mcl-1 in a dose- and cell line-dependent manner. While U373, LN18, LNZ428, T98G, LN229, and LNZ308 cells exhibited an IC(50) of 10 to 75 nmol/L, A172 cells were resistant (IC(50) ∼ 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 caspase-dependent apoptosis. Downregulation of Mcl-1 using short hairpin RNA also enhanced ABT-737-inducing killing, confirming an important role for Mcl-1 in mediating synergism between ABT-737 and YM-155. As with 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.

Medical Subject Headings

Apoptosis (drug effects); Biphenyl Compounds (pharmacology); Brain Neoplasms (drug therapy, genetics, metabolism); Cell Line, Tumor; Down-Regulation; Drug Resistance, Neoplasm (genetics); ErbB Receptors (antagonists & inhibitors, genetics, metabolism); Gene Expression Regulation, Neoplastic (drug effects); Glioma (drug therapy, genetics, metabolism); Humans; Imidazoles (pharmacology); Inhibitor of Apoptosis Proteins (antagonists & inhibitors, genetics, metabolism); Microtubule-Associated Proteins (genetics, metabolism); Myeloid Cell Leukemia Sequence 1 Protein; Naphthoquinones (pharmacology); Nitrophenols (pharmacology); Piperazines (pharmacology); Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, genetics, metabolism); Signal Transduction; Sulfonamides (pharmacology); Survivin; bcl-X Protein (antagonists & inhibitors, genetics, metabolism)

Publication Date

3-1-2013

Publication Title

Molecular cancer therapeutics

E-ISSN

1538-8514

Volume

12

Issue

3

First Page

326

Last Page

38

PubMed ID

23325792

Digital Object Identifier (DOI)

10.1158/1535-7163.MCT-12-0901

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