Vitamin E analogs, a novel group of "mitocans," as anticancer agents: the importance of being redox-silent.
The search for a selective and efficient anticancer agent for treating all neoplastic disease has yet to deliver a universally suitable compound(s). The majority of established anticancer drugs either are nonselective or lose their efficacy because of the constant mutational changes of malignant cells. Until recently, a largely neglected target for potential anticancer agents was the mitochondrion, showing a considerable promise for future clinical applications. Vitamin E (VE) analogs, epitomized by alpha-tocopheryl succinate, belong to the group of "mitocans" (mitochondrially targeted anticancer drugs). They are selective for malignant cells, cause destabilization of their mitochondria, and suppress cancer in preclinical models. This review focuses on our current understanding of VE analogs in the context of their proapoptotic/anticancer efficacy and suggests that their effect on mitochondria may be amplified by modulation of alternative pathways operating in parallel. We show here that the analogs of VE that cause apoptosis (which translates into their anticancer efficacy) generally do not possess antioxidant (redox) activity and are prototypical of the mitocan group of anticancer compounds. Therefore, by analogy to Oscar Wilde's play The Importance of Being Earnest, we use the motto in the title "the importance of being redox-silent" to emphasize an essentially novel paradigm for cancer therapy, in which redox-silence is a prerequisite property for most of the anticancer activities described in this communication.
Neuzil
Jiri
J
Apoptosis Research Group, Heart Foundation Research Centre, School of Medical Science, Griffith University Gold Coast Campus, Southport, Queensland, Australia. j.neuzil@griffith.edu.au
Tomasetti
Marco
M
Zhao
Yan
Y
Dong
Lan-Feng
LF
Birringer
Marc
M
Wang
Xiu-Fang
XF
Low
Pauline
P
Wu
Kun
K
Salvatore
Brian A
BA
Ralph
Steven J
SJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects*; D010084:Oxidation-Reduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D014810:Vitamin E