Effect of α-Tocopherol Succinate on Free Radical and Lipid Peroxidation Levels in BL6 Melanoma Cells

Ottino, Paulo; Duncan, J.R.

doi:10.1016/s0891-5849(96)00529-1

Cited by 96 publications

(59 citation statements)

References 28 publications

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“…Treatment of cells with ␣-TOS causes generation of ROS (Ottino and Duncan, 1997;Kogure et al, 2001Kogure et al, , 2002Weber et al, 2003;Stapelberg et al, 2005;Swettenham et al, 2005;Wang et al, 2005). Generation of ROS is an early event occurring in cells in response to VE analogs, and we have observed the accumulation of ROS in Jurkat T lymphoma cells within 1 h of treatment with ␣-TOS.…”

Section: Molecular Mechanism Of Apoptosis Induced By Ve Analogs the Rsupporting

confidence: 54%

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

Neužil¹,

Tomasetti²,

Zhao³

et al. 2007

Mol Pharmacol

126

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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...

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Section: Molecular Mechanism Of Apoptosis Induced By Ve Analogs the Rsupporting

confidence: 54%

“…The apoptotic action of ␣-TOS may also be initiated and/or amplified by ROS, generated during the cellular response to the agent (Ottino and Duncan, 1997;Kogure et al, 2001).…”

Section: Molecular Mechanism Of Apoptosis Induced By Ve Analogs the Rmentioning

confidence: 99%

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

Neužil¹,

Tomasetti²,

Zhao³

et al. 2007

Mol Pharmacol

126

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“…11,12 This latter process often involves the formation of ROS, release of cytochrome c and activation of multiple caspases. 13 Indeed, the generation of ROS in response to TOS could be directly detected by electron paramagnetic resonance spectroscopy in THP cells, 12 and TOS-induced generation of ROS in murine melanoma cells 14 and human lymphoma Jurkat cells was followed by mitochondrial alterations and caspase activation. 12,15 Furthermore, in Jurkat cells, TOS-induced apoptosis via ROS generation could be blocked by a mitochondrially targeted form of coenzyme Q, which acts as an antioxidant in mitochondria.…”

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confidence: 99%

Role of reactive oxygen species in the induction of apoptosis by α‐tocopheryl succinate

Kang

Lee

Choi

et al. 2004

Intl Journal of Cancer

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Alpha-tocopheryl succinate (TOS), a vitamin E analog, is a promising anticancer agent due to its abilities to inhibit proliferation and to induce apoptosis in a variety of human malignant cell lines, while being relatively less active toward normal cells. However, the molecular mechanisms underlying the apoptotic effects of TOS are not precisely understood. Reports that TOS can generate reactive oxygen species (ROS) prompted us to investigate the role of ROS in TOS-induced apoptosis in cancer cells. We found that the human lung cancer A549 and H460 cell lines were much more sensitive to TOS-induced apoptosis than the human glioblastoma T98G and U87MG cell lines. Our data suggested that the differential TOS sensitivity was not caused by differences in the uptake and retention of TOS between TOS-sensitive and -resistant cancer cells. The differential ability of cancer cells to generate ROS in response to TOS appears to be an important factor in determining the susceptibility of cells to TOS-induced apoptosis. Our results further suggest that TOS-induced generation of ROS is involved in caspase-independent apoptosis. Taken together, our findings suggest an important role of ROS generation in TOS-induced, caspase-independent apoptosis of cancer cells.

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“…Possible explanations at present of the effect of vitamin E on cell proliferation include suppression of mesangial cell proliferation via the inhibition of intracellular signal transduction pathways [8, 9]; mediation of the effect on vascular smooth muscle cell proliferation through an enhancement of free radical scavenging [3, 6], and inhibition of increases in the cytosolic ratio of free NADH/NAD + , phospholipase D and protein kinase C activation [10, 11]. Vitamin E also induces apoptosis in breast, prostate, and erythroleukemia cells [12], and reduces DNA synthesis in squamous carcinoma cells [13].…”

Section: Discussionmentioning

confidence: 99%

“…However, vitamin E can prevent to a limited extent the antiproliferative effects of alpha-linolenic and eicosapentaenoic acids on myeloma cells in vitro [4]. Considering that vitamin E also has a direct effect, which is concentration-dependent and cell specific, on proliferation of some cell lines [5]not only as a consequence of its antioxidant properties [6], it is necessary to rule out this direct effect of vitamin E when drawing conclusions in studies on cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

Vitamin E Inhibits Proliferation of Primary Cultured Human Mesangial and Endothelial Cells

Zhang

Yasumoto

Mei

et al. 2001

Nephron

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Background: Vitamin E (VE) has been used as an antioxidant and has been suggested to inhibit the proliferation of mesangial cells in rat and vascular endothelial cells. The direct effect of VE on primary cultures of mesangial cells (MC) and endothelial cells (EC) from the human glomerulus was studied. Methods: (1) MC (in 17 or 2.5% FCS DMEM) or EC (in 10 or 5% FCS CSC) at 5,000 cells/well was incubated with serial concentrations of VE from 0.05 to 50 µg/ml (0.06 to 60 IU/l). (2) MC was cocultured with 160, 80, 40 or 20 µg/ml of low-density lipoprotein (LDL) or oxidized LDL (ox-LDL) in 17 or 2.5% FCS DMEM with or without VE. After 3 days of incubation at 37°C in 5% CO₂, cell proliferation was measured by the Premix WST-1 Assay System. Results: The concentration of VE that significantly inhibited the proliferation of MC cultured in 17 or 2.5% FCS DMEM was 50 or 2.5 µg/ml (60 or 3.0 IU/l), respectively, and that of EC in 10 or 5% FCS medium was 50 or 25 µg/ml (60 or 30 IU/l). VE at 25 µg/ml (30 IU/l) inhibited the LDL proliferative effect on MC cultured in 2.5 FCS DMEM by 21.79–93.21% in a LDL concentration-dependent manner. There was little difference between the effects of LDL and ox-LDL on the VE inhibitory effect on MC under our experimental conditions. Conclusion: VE at low concentrations had no effect on the proliferation of both MC and EC, but at high concentrations, it showed an inhibitory effect on both cells.

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Effect of α-Tocopherol Succinate on Free Radical and Lipid Peroxidation Levels in BL6 Melanoma Cells

Cited by 96 publications

References 28 publications

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

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

Role of reactive oxygen species in the induction of apoptosis by α‐tocopheryl succinate

Vitamin E Inhibits Proliferation of Primary Cultured Human Mesangial and Endothelial Cells

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