MINIREVIEW Vitamin E Analogs, a Novel Group of “Mitocans,” as Anticancer Agents: The Importance of Being Redox-Silent Jiri Neuzil, Marco Tomasetti, Yan Zhao, Lan-Feng Dong, Marc Birringer, Xiu-Fang Wang, Pauline Low, Kun Wu, Brian A. Salvatore, and Steven J. Ralph Apoptosis Research Group, School of Medical Science, Griffith University, Southport, Queensland, Australia (J.N., L.F.D., X.F.W.); Molecular Therapy Group, Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic (J.N.); Department of Nutrition and Food, Harbin Medical University, Harbin, Heilongjiang Province, China (Y.Z., K.W.); Department of Molecular Pathology and Innovative Therapies, Polytechnic University of Marche, Ancona, Italy (M.T.); Institute of Human Nutrition, Friedrich Schiller University, Jena, Germany (M.B.); Genomic Research Centre, School of Medical Science, Griffith University, Southport, Queensland, Australia (P.L., S.J.R.); and Department of Chemistry and Physics, Louisiana State University, Shreveport, Louisiana (B.A.S.) Received August 22, 2006; accepted January 10, 2007 ABSTRACT 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 re- cently, 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 -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. Despite advances in molecular medicine, the third millen- nium has borne witness to neoplastic disease becoming a major cause for mortality in developed countries. Moreover, fast-growing economies in countries like India and China are likely to be severely affected by cancer in a decade or so as a result of heavy industrialization. Certain types of cancer, such as malignant mesothelioma (MM), seem to remain be- yond the realms of treatment. In many other cases, muta- tions arise in the tumors, seriously compromising the out- come of the therapy. For example, in breast cancer, in which a high frequency of overexpression of the tyrosine receptor kinase erbB2 occurs, this is often associated with resistance to chemotherapy (Xia et al., 2006). We are therefore in need of treatment modalities that would overcome these problems and that are efficient, selective, and readily available to all Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org. doi:10.1124/mol.106.030122. ABBREVIATIONS: MM, malignant mesothelioma; BH, Bcl-2 homology; DHFR, dihydrofolate reductase; DR, death receptor; ERK, extracellular signal-regulated protein kinase; FLIP, Fas-associated death domain-like interleukin-1-converting enzyme-inhibitory protein; IAP, inhibitor of apoptosis protein; IB, inhibitory subunit of nuclear factor B; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MPTP, mitochondrial permeability transition pore; MTX, methotrexate; NFB, nuclear factor-B; OS, osteosarcoma; PKC, protein kinase C; PP2A, protein phosphatase 2A; ROS, reactive oxygen species; SAR, structure-activity relationship; SMase, sphingomyelinase; TNF, tumor necrosis factor; -TOS, -tocopheryl succinate; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; UbQ, ubiquinone; VDAC, voltage-dependent anionic channel; VE, vitamin E; CD437, 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid; 2DG, 2-deoxyglucose; DR4, tumor necrosis factor-related apoptosis-inducing ligand receptor 1; DR5, tumor necrosis factor-related apoptosis-inducing ligand receptor 2. 0026-895X/07/7105-1185–1199$20.00 MOLECULAR PHARMACOLOGY Vol. 71, No. 5 Copyright © 2007 The American Society for Pharmacology and Experimental Therapeutics 30122/3190523 Mol Pharmacol 71:1185–1199, 2007 Printed in U.S.A. 1185 at ASPET Journals on September 13, 2015 molpharm.aspetjournals.org Downloaded from