Mitochondrial bioenergetics as a cell fate rheostat for responsive to Bcl-2 drugs: New cues for cancer chemotherapy

• Published in: Cancer letters Vol. 594; p. 216965
• Main Authors: Palominos, Charlotte, Fuentes-Retamal, Sebastián, Salazar, Juan Pablo, Guzmán-Rivera, Daniela, Correa, Pablo, Mellado, Mathias, Araya-Maturana, Ramiro, Urra, Félix A.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 10-07-2024
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cancer metabolism; Drug Resistance, Neoplasm - drug effects; Energy Metabolism - drug effects; Humans; Intrinsic apoptosis pathway; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitophagy; Navitoclax; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Oxidative phosphorylation; Proto-Oncogene Proteins c-bcl-2 - metabolism; Venetoclax; Mitochondria; Oxidative phosphorylation; Cancer metabolism; Navitoclax; Intrinsic apoptosis pathway; Mitophagy; Venetoclax
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2024.216965

Pro-survival BCL-2 proteins prevent the initiation of intrinsic apoptosis (mitochondria-dependent pathway) by inhibiting the pro-apoptotic proteins BAX and BAK, while BH3-only proteins promote apoptosis by blocking pro-survival BCL-2 proteins. Disruptions in this delicate balance contribute to cancer cell survival and chemoresistance. Recent advances in cancer therapeutics involve a new generation of drugs known as BH3-mimetics, which are small molecules designed to mimic the action of BH3-only proteins. Promising effects have been observed in patients with hematological and solid tumors undergoing treatment with these agents. However, the rapid emergence of mitochondria-dependent resistance to BH3-mimetics has been reported. This resistance involves increased mitochondrial respiration, altered mitophagy, and mitochondria with higher and tighter cristae. Conversely, mutations in isocitrate dehydrogenase 1 and 2, catalyzing R-2-hydroxyglutarate production, promote sensitivity to venetoclax. This evidence underscores the urgency for comprehensive studies on bioenergetics-based adaptive responses in both BH3 mimetics-sensitive and -resistant cancer cells. Ongoing clinical trials are evaluating BH3-mimetics in combination with standard chemotherapeutics. In this article, we discuss the role of mitochondrial bioenergetics in response to BH3-mimetics and explore potential therapeutic opportunities through metabolism-targeting strategies.
•Drugs targeting BCL-2 family proteins are in clinical use for leukemia and undergoing evaluation in solid cancers.•BH3-mimetics are small molecules designed to mimic the action of BH3-only proteins.•Increased mitochondrial bioenergetics contribute to resistance to BH3-mimetics.•Selective targeting of mutated IDH1/2 enzymes enhances the efficacy of BH3-mimetics.•Future strategies involving Complex I inhibitors may overcome resistance to Venetoclax.