Glioblastoma (GBM) is characterized by a poor response to conventional chemotherapeutic agents, attributed to the insurgence of drug resistance mechanisms and to the presence of a subpopulation of glioma stem cells (GSCs). GBM cells and GSCs present, among others, an overexpression of antiapoptotic proteins and an inhibition of pro-apoptotic ones, which help to escape apoptosis. Among pro-apoptotic inducers, the Bcl-2 family protein Bax has recently emerged as a promising new target in cancer therapy along with first BAX activators (BAM7, Compound 106, and SMBA1). Herein, a derivative of BAM-7, named BTC-8, was employed to explore the effects of Bax activation in different human GBM cells and in their stem cell subpopulation. BTC-8 inhibited GBM cell proliferation, arrested the cell cycle, and induced apoptosis through the induction of mitochondrial membrane permeabilization. Most importantly, BTC-8 blocked proliferation and self-renewal of GSCs and induced their apoptosis. Notably, BTC-8 was demonstrated to sensitize both GBM cells and GSCs to the alkylating agent Temozolomide. Overall, our findings shed light on the effects and the relative molecular mechanisms related to Bax activation in GBM, and they suggest Bax-targeting compounds as promising therapeutic tools against the GSC reservoir.

Bax activation blocks self-renewal and induces apoptosis of human glioblastoma stem cells / Daniele, S.; Pietrobono, D.; Costa, B.; Giustiniano, M.; La Pietra, V.; Giacomelli, C.; LA REGINA, Giuseppe; Silvestri, Romano; Taliani, S.; Trincavelli, M. L.; Da Settimo, F.; Novellino, E.; Martini, C.; Marinelli, L.. - In: ACS CHEMICAL NEUROSCIENCE. - ISSN 1948-7193. - STAMPA. - 9:1(2018), pp. 85-99. [10.1021/acschemneuro.7b00023]

Bax activation blocks self-renewal and induces apoptosis of human glioblastoma stem cells

LA REGINA, GIUSEPPE;SILVESTRI, Romano;
2018

Abstract

Glioblastoma (GBM) is characterized by a poor response to conventional chemotherapeutic agents, attributed to the insurgence of drug resistance mechanisms and to the presence of a subpopulation of glioma stem cells (GSCs). GBM cells and GSCs present, among others, an overexpression of antiapoptotic proteins and an inhibition of pro-apoptotic ones, which help to escape apoptosis. Among pro-apoptotic inducers, the Bcl-2 family protein Bax has recently emerged as a promising new target in cancer therapy along with first BAX activators (BAM7, Compound 106, and SMBA1). Herein, a derivative of BAM-7, named BTC-8, was employed to explore the effects of Bax activation in different human GBM cells and in their stem cell subpopulation. BTC-8 inhibited GBM cell proliferation, arrested the cell cycle, and induced apoptosis through the induction of mitochondrial membrane permeabilization. Most importantly, BTC-8 blocked proliferation and self-renewal of GSCs and induced their apoptosis. Notably, BTC-8 was demonstrated to sensitize both GBM cells and GSCs to the alkylating agent Temozolomide. Overall, our findings shed light on the effects and the relative molecular mechanisms related to Bax activation in GBM, and they suggest Bax-targeting compounds as promising therapeutic tools against the GSC reservoir.
2018
bax activation; bcl-2 family; cancer stem cells; glioblastoma; pro-apoptotic proteins
01 Pubblicazione su rivista::01a Articolo in rivista
Bax activation blocks self-renewal and induces apoptosis of human glioblastoma stem cells / Daniele, S.; Pietrobono, D.; Costa, B.; Giustiniano, M.; La Pietra, V.; Giacomelli, C.; LA REGINA, Giuseppe; Silvestri, Romano; Taliani, S.; Trincavelli, M. L.; Da Settimo, F.; Novellino, E.; Martini, C.; Marinelli, L.. - In: ACS CHEMICAL NEUROSCIENCE. - ISSN 1948-7193. - STAMPA. - 9:1(2018), pp. 85-99. [10.1021/acschemneuro.7b00023]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/954245
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