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1. 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.

Author

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

Subjects
*PHOSPHOINOSITIDES, *MTOR protein, *GENE expression, *OVARIAN cancer treatment, *CANCER cells, *APOPTOSIS, *B cells
Abstract

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. [Copyright &y& Elsevier]

Published
2014
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