TY - JOUR
T1 - Mitochondrial bioenergetics as a cell fate rheostat for responsive to Bcl-2 drugs
T2 - New cues for cancer chemotherapy
AU - Palominos, Charlotte
AU - Fuentes-Retamal, Sebastián
AU - Salazar, Juan Pablo
AU - Guzmán-Rivera, Daniela
AU - Correa, Pablo
AU - Mellado, Mathias
AU - Araya-Maturana, Ramiro
AU - Urra, Félix A.
N1 - Publisher Copyright:
© 2024 Elsevier B.V.
PY - 2024/7/10
Y1 - 2024/7/10
N2 - 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.
AB - 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.
KW - Cancer metabolism
KW - Intrinsic apoptosis pathway
KW - Mitochondria
KW - Mitophagy
KW - Navitoclax
KW - Oxidative phosphorylation
KW - Venetoclax
UR - http://www.scopus.com/inward/record.url?scp=85194311703&partnerID=8YFLogxK
U2 - 10.1016/j.canlet.2024.216965
DO - 10.1016/j.canlet.2024.216965
M3 - Review article
C2 - 38788967
AN - SCOPUS:85194311703
SN - 0304-3835
VL - 594
JO - Cancer Letters
JF - Cancer Letters
M1 - 216965
ER -