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

Esther P. Jane, Daniel R. Premkumar, Joseph D. DiDomenico, Bo Hu, Shi-Yuan Cheng, Ian F. Pollack*

*Corresponding author for this work

Research output: Contribution to journalArticle

28 Citations (Scopus)

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 LNZ308cells 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 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.

Original languageEnglish (US)
Pages (from-to)326-338
Number of pages13
JournalMolecular cancer therapeutics
Volume12
Issue number3
DOIs
StatePublished - Mar 1 2013

Fingerprint

Epidermal Growth Factor Receptor
Down-Regulation
Glioma
Apoptosis
Inhibitory Concentration 50
ABT-737
YM 155
Cell Line
Small Interfering RNA
Therapeutics
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

@article{4ac42c7f36134503ae3869ea8879ca7a,
title = "YM-155 potentiates the effect of ABT-737 in malignant humanglioma cells via survivin and Mcl-1 downregulation in an EGFR-dependent context",
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 LNZ308cells 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 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.",
author = "Jane, {Esther P.} and Premkumar, {Daniel R.} and DiDomenico, {Joseph D.} and Bo Hu and Shi-Yuan Cheng and Pollack, {Ian F.}",
year = "2013",
month = "3",
day = "1",
doi = "10.1158/1535-7163.MCT-12-0901",
language = "English (US)",
volume = "12",
pages = "326--338",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "3",

}

YM-155 potentiates the effect of ABT-737 in malignant humanglioma cells via survivin and Mcl-1 downregulation in an EGFR-dependent context. / Jane, Esther P.; Premkumar, Daniel R.; DiDomenico, Joseph D.; Hu, Bo; Cheng, Shi-Yuan; Pollack, Ian F.

In: Molecular cancer therapeutics, Vol. 12, No. 3, 01.03.2013, p. 326-338.

Research output: Contribution to journalArticle

TY - JOUR

T1 - YM-155 potentiates the effect of ABT-737 in malignant humanglioma cells via survivin and Mcl-1 downregulation in an EGFR-dependent context

AU - Jane, Esther P.

AU - Premkumar, Daniel R.

AU - DiDomenico, Joseph D.

AU - Hu, Bo

AU - Cheng, Shi-Yuan

AU - Pollack, Ian F.

PY - 2013/3/1

Y1 - 2013/3/1

N2 - 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 LNZ308cells 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 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.

AB - 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 LNZ308cells 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 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.

UR - http://www.scopus.com/inward/record.url?scp=84874854237&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84874854237&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-12-0901

DO - 10.1158/1535-7163.MCT-12-0901

M3 - Article

C2 - 23325792

AN - SCOPUS:84874854237

VL - 12

SP - 326

EP - 338

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 3

ER -