Molecular mechanism of 'mitocan'-induced apoptosis in cancer cells epitomizes the multiple roles of reactive oxygen species and Bcl-2 family proteins.
Mitochondria have emerged recently as effective targets for novel anti-cancer drugs referred to as 'mitocans'. We propose that the molecular mechanism of induction of apoptosis by mitocans, as exemplified by the drug alpha-tocopheryl succinate, involves generation of reactive oxygen species (ROS). ROS then mediate the formation of disufide bridges between cytosolic Bax monomers, resulting in the formation of mitochondrial outer membrane channels. ROS also cause oxidation of cardiolipin, triggering the release of cytochrome c and its translocation via the activated Bax channels. This model may provide a general mechanism for the action of inducers of apoptosis and anticancer drugs, mitocans, targeting mitochondria via ROS production.
Neuzil
Jiri
J
Apoptosis Research Group, School of Medical Science, Griffith University, Southport, Qld, Australia. j.neuzil@griffith.edu.au
Wang
Xiu-Fang
XF
Dong
Lan-Feng
LF
Low
Pauline
P
Ralph
Stephen J
SJ
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002308:Cardiolipins / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D017382:Reactive Oxygen Species; D024505:Tocopherols; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
D000970:Antineoplastic Agents; D002308:Cardiolipins; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D014810:Vitamin E; D045304:Cytochromes c; D024505:Tocopherols