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

Abdelghani Jebahi; Marie Villedieu; Cécile Pétigny-Lechartier; Emilie Brotin; Marie-Hélène Louis; Edwige Abeilard; Florence Giffard; Marika Guercio; Mélanie Briand; Pascal Gauduchon; Stéphanie Lheureux; Laurent Poulain

doi:10.1016/j.canlet.2014.03.001

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.

Affiliations

¹ Normandy University, France; UNICAEN, "Biology and Innovative Therapeutics of Locally Aggressive Cancers" Unit (EA 4656), Caen, France; François Baclesse Comprehensive Cancer Centre, Caen, France.
² Normandy University, France; UNICAEN, "Biology and Innovative Therapeutics of Locally Aggressive Cancers" Unit (EA 4656), Caen, France; François Baclesse Comprehensive Cancer Centre, Caen, France; (d)On secondment from ISPB, Faculte de Pharmacie, Universite Lyon 1, Lyon, France. Electronic address: [email protected].
³ Normandy University, France; UNICAEN, "Biology and Innovative Therapeutics of Locally Aggressive Cancers" Unit (EA 4656), Caen, France.
⁴ Normandy University, France; UNICAEN, "Biology and Innovative Therapeutics of Locally Aggressive Cancers" Unit (EA 4656), Caen, France; François Baclesse Comprehensive Cancer Centre, Caen, France; Clinical Research Department, François Baclesse Comprehensive Cancer Centre, Caen, France; Oncologic Uro-Gynaecology Department, François Baclesse Comprehensive Cancer Centre, Caen, France.

PMID: 24650799
DOI: 10.1016/j.canlet.2014.03.001

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