PI3K/mTOR dual inhibitor NVP-BEZ235 decreases Mcl-1 expression and sensitizes ovarian carcinoma cells to Bcl-xL-targeting strategies, provided that Bim expression is induced

Cancer Lett. 2014 Jun 28;348(1-2):38-49. doi: 10.1016/j.canlet.2014.03.001. Epub 2014 Mar 18.

Abstract

We previously showed that Bcl-xL and Mcl-1 cooperatively protect platinum-resistant ovarian cancer cells from apoptosis. Here we assessed the anticancer potential of combining ABT-737-induced inhibition of Bcl-xL with Mcl-1 inhibition via PI3K/Akt/mTOR pathway disruption using NVP-BEZ235. NVP-BEZ235 inhibited cell proliferation without inducing apoptosis. It strongly repressed Mcl-1 expression and induced Puma expression in both cell lines tested while differentially modulating Bim between the two. Interestingly, NVP-BEZ235 efficiently sensitized ovarian carcinoma cells to ABT-737, provided that Bim expression was induced. Moreover, inhibiting the ERK1/2 pathway restored Bim expression and sensitized low Bim-expressing cancer cells to the BEZ235/ABT-737 treatment.

Keywords: ABT-737; Bim; ERK1/2; Mcl-1; NVP-BEZ235; Ovarian cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Bcl-2-Like Protein 11
  • Biphenyl Compounds / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Imidazoles / pharmacology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors*
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Nitrophenols / pharmacology
  • Ovarian Neoplasms / enzymology*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / pathology
  • Phosphatidylinositol 3-Kinase / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Piperazines / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Quinolines / pharmacology
  • RNA Interference
  • Signal Transduction / drug effects
  • Sulfonamides / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / metabolism
  • Time Factors
  • Transfection
  • bcl-X Protein / antagonists & inhibitors*
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism

Substances

  • ABT-737
  • Apoptosis Regulatory Proteins
  • BBC3 protein, human
  • BCL2L1 protein, human
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Biphenyl Compounds
  • Imidazoles
  • MCL1 protein, human
  • Membrane Proteins
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Nitrophenols
  • PMAIP1 protein, human
  • Phosphoinositide-3 Kinase Inhibitors
  • Piperazines
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Quinolines
  • Sulfonamides
  • bcl-X Protein
  • MTOR protein, human
  • Phosphatidylinositol 3-Kinase
  • TOR Serine-Threonine Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • dactolisib