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

Mol Cancer Ther. 2013 Mar;12(3):326-38. doi: 10.1158/1535-7163.MCT-12-0901. Epub 2013 Jan 16.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • ABT-737
  • BIRC5 protein, human
  • Biphenyl Compounds
  • Imidazoles
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Naphthoquinones
  • Nitrophenols
  • Piperazines
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides
  • Survivin
  • YM 155
  • bcl-X Protein
  • EGFR protein, human
  • ErbB Receptors