Vitamin E Analogs, a Novel Group of “Mitocans,” as Anticancer Agents: The Importance of Being Redox-Silent

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 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 ␣-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 redoxsilence is a prerequisite property for most of the anticancer activities described in this communication.Despite advances in molecular medicine, the third millennium 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 beyond the realms of treatment. In many other cases, mutations arise in the tumors, seriously compromising the outcome 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; IB, inhibitory subunit of nuclear factor B; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MPTP, mitochondrial permeability transition pore; MTX, methotrexate; NFB, nuclear factor-B; O...

α-Tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II

“…Studies with mitocans have shown exciting potential for cancer therapy since these drugs have limited side effects, and some of these compounds possess specificity for cancer cells (Neuzil et al, 2007).…”

“…Cytotoxic drugs acting by selectively affecting mitochondria in cancer cells, 'mitocans' (Neuzil et al, 2006(Neuzil et al, , 2007Ralph et al, 2007), are attractive for the treatment of cancer (Ko et al, 2004;Bonnet et al, 2007;Dong et al, 2007;Neuzil et al, 2007). Prime examples of such drugs are a-tocopheryl succinate (a-TOS) (Neuzil et al, 2001a, b), 3-bromopyruvate (3BP) (Geschwind et al, 2002;Ko et al, 2004) and dichloroacetate (DCA) (Bonnet et al, 2007).…”

(+)α-Tocopheryl succinate inhibits the mitochondrial respiratory chain complex I and is as effective as arsenic trioxide or ATRA against acute promyelocytic leukemia in vivo

“…6,7 Both a-TOS and ATO have been described as anticancer drugs that target mitochondria (known as mitocans), which are thought to exert their cytotoxic effects primarily by interfering with the generation of reactive oxygen species (ROS). 8 Indeed, the exquisite sensitivity of APL to ATO treatment has been recently demonstrated to be mediated by PML-RARa oxidation and subsequent degradation in an ROS-dependent process. 9 Interestingly, Weber et al 10 demonstrated that p0 cells that lack mitochondrial respiratory chain (MRC) activity are insensitive to a-TOS toxicity.…”

α-Tocopheryl succinate promotes selective cell death induced by vitamin K3 in combination with ascorbate

“…a-TOS, a compound epitomising the 'mitocan' group of anticancer agents (Neuzil et al, 2007a), was found to induce cell death by generation of superoxide anion radicals by targeting complex II of the mitochondria respiratory chain (Dong et al, 2008(Dong et al, , 2009. ROS, in turn, promote apoptosis by catalysing the formation of disulfite bridges between monomeric Bax, resulting in the formation of mitochondrial outer membrane channel.…”

“…One of the emerging targets for anti-cancer drugs is mitochondria that is central to induction of programmed cell death (Gogvadze et al, 2008;Trachootham et al, 2009). Our previous work has identified mitochondria as transmitters of apoptosis induced by the redox-silent analogue of vitamin E (VE) a-tocopheryl succinate (a-TOS) (Neuzil et al, , 2007a) that is selective for cancer cells (Neuzil et al, 2001a, b) and suppresses tumours in a variety of pre-clinical models (Neuzil et al, 2001b;Stapelberg et al, 2005;Wang et al, 2007;Dong et al, 2008Dong et al, , 2009). This suggests that the VE analogue is a promising anti-cancer drug that may suppress tumours by causing cell death of malignant cells as well as synergizing with other anti-cancer agents.…”