Cancer chemoprevention and mitochondria: targeting apoptosis in transformed cells via the disruption of mitochondrial bioenergetics/redox state.
Cancer chemoprevention employs agents that block, hinder, or reverse tumorigenesis to prevent malignancy. Several putative cancer chemopreventive agents promote apoptosis in transformed cells initiated in animal carcinogenesis models or identified in human subjects, and/or in tumor cells cultured in vitro. Consequently, apoptosis induction is increasingly valued as a biologically significant anticancer mechanism in the arena of chemoprevention. In vitro studies suggest that the permeabilization of mitochondrial membranes is an important mechanistic determinant associated with the apoptosis induced by these agents. Mitochondrial membrane permeabilization (MMP) may occur via the control of proapoptotic Bcl-2 family members, and/or by the induction of the mitochondrial permeability transition. Both of these cell death-inducing regulatory mechanisms are ultimately responsive to the bioenergetic status/redox state of mitochondria. Interestingly, in addition to inducing MMP, various chemopreventive agents can directly modulate mitochondrial bioenergetics and/or redox tone in transformed cells. This review will examine prospective mechanisms associated with the disruption of mitochondrial function by chemopreventive agents that affect MMP and apoptosis. In doing so, we will construct a paradigm supporting the notion that the bioenergetic and/or redox characteristics of the mitochondria in transformed cells are important targets in the chemoprevention of cancer.
Hail
Numsen
N
Department of Pharmaceutical Sciences, The University of Colorado Denver School of Pharmacy, Aurora, CO 80045, USA. numsen.hail@uchsc.edu
Lotan
Reuben
R
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002211:Capsaicin / Q000627:therapeutic use; D002392:Catechin / Q000627:therapeutic use; D018890:Chemoprevention / Q000379:methods*; D004195:Disease Models, Animal; D006801:Humans; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy / Q000517:prevention & control*; D010539:Permeability; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000627:therapeutic use; D013662:Tea
D017382:Reactive Oxygen Species; D013267:Stilbenes; D013662:Tea; D002392:Catechin; D000077185:Resveratrol; D002211:Capsaicin