title: Bax Activation Blocks Self-Renewal and Induces Apoptosis of Human Glioblastoma Stem Cells.
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.
authors.affiliation: Department of Pharmacy, University of Pisa , 56126 Pisa, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Daniele
authors.affiliation: Department of Pharmacy, University of Pisa , 56126 Pisa, Italy.
authors.forename: Deborah
authors.initials: D
authors.lastname: Pietrobono
authors.affiliation: Department of Pharmacy, University of Pisa , 56126 Pisa, Italy.
authors.forename: Barbara
authors.identifier: 0000-0002-7598-1275
authors.initials: B
authors.lastname: Costa
authors.affiliation: Department of Pharmacy, University of Naples Federico II , 80131 Napoli, Italy.
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Giustiniano
authors.affiliation: Department of Pharmacy, University of Naples Federico II , 80131 Napoli, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: La Pietra
authors.affiliation: Department of Pharmacy, University of Pisa , 56126 Pisa, Italy.
authors.forename: Chiara
authors.identifier: 0000-0002-6244-602X
authors.initials: C
authors.lastname: Giacomelli
authors.affiliation: Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma , 00185 Roma, Italy.
authors.forename: Giuseppe
authors.identifier: 0000-0003-3252-1161
authors.initials: G
authors.lastname: La Regina
authors.affiliation: Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma , 00185 Roma, Italy.
authors.forename: Romano
authors.identifier: 0000-0003-2489-0178
authors.initials: R
authors.lastname: Silvestri
authors.affiliation: Department of Pharmacy, University of Pisa , 56126 Pisa, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Taliani
authors.affiliation: Department of Pharmacy, University of Pisa , 56126 Pisa, Italy.
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Trincavelli
authors.affiliation: Department of Pharmacy, University of Pisa , 56126 Pisa, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Da Settimo
authors.affiliation: Department of Pharmacy, University of Naples Federico II , 80131 Napoli, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: Department of Pharmacy, University of Pisa , 56126 Pisa, Italy.
authors.forename: Claudia
authors.identifier: 0000-0001-9379-3027
authors.initials: C
authors.lastname: Martini
authors.affiliation: Department of Pharmacy, University of Naples Federico II , 80131 Napoli, Italy.
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D016543:Central Nervous System Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004359:Drug Therapy, Combination; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011720:Pyrazoles / Q000494:pharmacology; D000077204:Temozolomide; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C494826:BAX protein, human; D006835:Hydrazones; D011720:Pyrazoles; D051028:bcl-2-Associated X Protein; D003606:Dacarbazine; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D000077204:Temozolomide
keywords: Bax activation; Bcl-2 family; cancer stem cells; glioblastoma; pro-apoptotic proteins