PT - JOURNAL ARTICLE AU - Jiri Neuzil AU - Marco Tomasetti AU - Yan Zhao AU - Lan-Feng Dong AU - Marc Birringer AU - Xiu-Fang Wang AU - Pauline Low AU - Kun Wu AU - Brian A. Salvatore AU - Steven J. Ralph TI - Vitamin E Analogs, a Novel Group of “Mitocans,” as Anticancer Agents: The Importance of Being Redox-Silent AID - 10.1124/mol.106.030122 DP - 2007 May 01 TA - Molecular Pharmacology PG - 1185--1199 VI - 71 IP - 5 4099 - http://molpharm.aspetjournals.org/content/71/5/1185.short 4100 - http://molpharm.aspetjournals.org/content/71/5/1185.full SO - Mol Pharmacol2007 May 01; 71 AB - 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 α-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. The American Society for Pharmacology and Experimental Therapeutics