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Molecular Pharmacology

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OtherMINIREVIEW

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
Molecular Pharmacology May 2007, 71 (5) 1185-1199; DOI: https://doi.org/10.1124/mol.106.030122
Jiri Neuzil
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Marco Tomasetti
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Yan Zhao
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Lan-Feng Dong
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Marc Birringer
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Xiu-Fang Wang
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Pauline Low
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Kun Wu
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Brian A. Salvatore
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Steven J. Ralph
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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 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.

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  • 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-1β-converting enzyme-inhibitory protein; IAP, inhibitor of apoptosis protein; IκB, inhibitory subunit of nuclear factor κB; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MPTP, mitochondrial permeability transition pore; MTX, methotrexate; NFκB, nuclear factor-κB; OS, osteosarcoma; PKC, protein kinase C; PP2A, protein phosphatase 2A; ROS, reactive oxygen species; SAR, structure-activity relationship; SMase, sphingomyelinase; TNF, tumor necrosis factor; α-TOS, α-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.

    • Received August 22, 2006.
    • Accepted January 10, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 71 (5)
Molecular Pharmacology
Vol. 71, Issue 5
1 May 2007
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OtherMINIREVIEW

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
Molecular Pharmacology May 1, 2007, 71 (5) 1185-1199; DOI: https://doi.org/10.1124/mol.106.030122

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OtherMINIREVIEW

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
Molecular Pharmacology May 1, 2007, 71 (5) 1185-1199; DOI: https://doi.org/10.1124/mol.106.030122
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    • Structure-Function Relationship of Proapoptotic/Antineoplastic VE Analogs
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