Mitocans as anti-cancer agents targeting mitochondria: lessons from studies with vitamin E analogues, inhibitors of complex II.
Recently mitochondria in cancer cells have emerged as the Achilles heel for tumour destruction. Anti-cancer agents specifically targeting cancer cell mitochondria are referred to as 'mitocans'. These compounds act by destabilising these organelles, unleashing their apoptogenic potential, resulting in the efficient death of malignant cells and suppression of tumour growth. Importantly, at least some mitocans are selective for cancer cells, and these are represented by the group of redox-silent vitamin E analogues, epitomised by alpha-tocopheryl succinate (alpha-TOS). This compound has proven itself in pre-clinical models to be an efficient anti-cancer agent, targeting complex II of the respiratory chain to displace ubiquinone binding. We propose that disrupting the electron flow of mitochondrial complex II results in generation of superoxide, triggering mitochondrial destabilisation and initiation of apoptotic pathways. Moreover, alpha-TOS is selective for cancer cells with their reduced anti-oxidant defenses and lower esterase activity than the normal (non-malignant) counterparts. In this mini-review we discuss the emerging significance of mitocans, as exemplified by alpha-TOS.
Neuzil
Jiri
J
Apoptosis Research Group, School of Medical Science, Griffith University, Southport, Qld, Australia. j.neuzil@griffith.edu.au
Dyason
Jeffrey C
JC
Freeman
Ruth
R
Dong
Lan-Feng
LF
Prochazka
Lubomir
L
Wang
Xiu-Fang
XF
Scheffler
Immo
I
Ralph
Stephen J
SJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D042963:Electron Transport Complex II / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014810:Vitamin E / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D013481:Superoxides; D014810:Vitamin E; D042963:Electron Transport Complex II