Vitamin E analogues as a novel group of mitocans: Anti-cancer agents that act by targeting mitochondria

Neužil, Jiřı́; Dong, Lan-Feng; Ramanathapuram, Lalitha; Hahn, Tobias; Chladova, Miroslava; Wang, Xiufang; Zobalova, Renata; Procházka, Lubomír; Gold, Mikhal; Freeman, Ruth; Tuřánek, Jaroslav; Akporiaye, Emmanuel T.; Dyason, Jeffrey Clifford; Ralph, Stephen John

doi:10.1016/j.mam.2007.02.003

Cited by 99 publications

(84 citation statements)

References 202 publications

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“…Mitocans are small compounds that exhibit anticancer activity by selectively inducing apoptosis by mitochondrial interference, comprising seven classes of agents with different modes of action (4). The class 5 mitocans include drugs that act by targeting the mitochondrial electron transport chain, of which the prime examples are vitamin E (VE) analogues, epitomized by the ester a-tocopheryl succinate (a-TOS; refs.…”

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confidence: 99%

Suppression of Tumor GrowthIn vivoby the Mitocan α-tocopheryl Succinate Requires Respiratory Complex II

Dong¹,

Freeman²,

Liu³

et al. 2009

Clinical Cancer Research

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Purpose: Vitamin E analogues are potent novel anticancer drugs. The purpose of this study was to elucidate the cellular target by which these agents, represented by a-tocopoheryl succinate (a-TOS), suppress tumors in vivo, with the focus on the mitochondrial complex II (CII). Experimental Design: Chinese hamster lung fibroblasts with functional, dysfunctional, and reconstituted CII were transformed using H-Ras. The cells were then used to form xenografts in immunocompromized mice, and response of the cells and the tumors to a-TOS was studied. Results: The CII-functional and CII-reconstituted cells, unlike their CII-dysfunctional counterparts, responded to a-TOS by reactive oxygen species generation and apoptosis execution. Tumors derived from these cell lines reciprocated their responses to a-TOS. Thus, growth of CII-functional and CII-reconstituted tumors was strongly suppressed by the agent, and this was accompanied by high level of apoptosis induction in the tumor cells. On the other hand, a-TOS did not inhibit the CII-dysfuntional tumors. Conclusions: We document in this report a novel paradigm, according to which the mitochondrial CII, which rarely mutates in human neoplasias, is a plausible target for anticancer drugs from the group of vitamin E analogues, providing support for their testing in clinical trials.

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confidence: 99%

Suppression of Tumor GrowthIn vivoby the Mitocan α-tocopheryl Succinate Requires Respiratory Complex II

Dong¹,

Freeman²,

Liu³

et al. 2009

Clinical Cancer Research

Self Cite

125

107

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“…However, the main limitation in vitamin E treatment is acute supplementation because marked lipophilicity hampers tissue distribution and therefore cellular bioavailability. Tocopherol esters may have advantages for processing, storage and absorption because of their greater stability and water solubility compared with tocopherol alone (Neuzil et al, 2007). They are usually rapidly converted to the natural forms by intestinal or epidermal esterases in the gastrointestinal tract, and thus can be considered to be pro-vitamins, ultimately performing the same functions in the body as natural α-tocopherol (Zingg, 2007).…”

Section: Introductionmentioning

confidence: 99%

Effect of RRR-α-tocopherol succinate on the meat quality and antioxidative status in broilers

Zhang¹,

Wang²,

Zhou³

et al. 2012

SA J. An. Sci.

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________________________________________________________________________________ AbstractThe objective of this study was to compare the effects of two esters of α-tocopherol, all-rac-α-tocopherol acetate (DL-α-TOA) and RRR-α-tocopherol succinate (D-α-TOS), on meat quality and the antioxidative status in chicks. A total of 320 day-old Arbor Acres broiler chicks were randomly allocated to 4 treatments, each consisting of 8 pens of 10 chicks per pen. Birds in the control group received the basal diet supplemented with 30 mg DL-α-TOA/kg diet. In the other treatments the diet was supplemented with D-α-TOS at 15 mg/kg, 30 mg/kg or 60 mg/kg (TOS1, TOS2 and TOS3 treatments), respectively. The trial lasted 42 days. Positive correlations existed between dietary D-α-TOS levels and plasma and hepatic α-tocopherol concentrations, and a negative correlation with malonaldehyde (MDA) concentrations. In comparison with the control group, 30 mg/kg and 60 mg/kg of dietary D-α-TOS supplementation resulted in an increase in glutathione peroxidase (GSH-Px) activity and glutathione (GSH) content of the breast and thigh muscle and total superoxide dismutase (T-SOD) activity in the thigh muscle. Furthermore, the muscle MDA and hepatic reactive oxygen species (ROS) levels were reduced. As for meat quality, 48 h drip loss and shear force of breast and leg muscle were lower in broilers in the TOS1, TOS2 treatments and also the cooking loss in leg muscle. The study suggests that 30 mg/kg to 60 mg D-α-TOS/kg of the diet could enhance the antioxidant capacity of broiler meat, and its water-holding capacity and tenderness, in association with the reduction in lipid peroxidation as measured as a decrease in MDA and ROS concentrations.________________________________________________________________________________

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“…TOS has also been shown to induce apoptosis by activating Fas signaling pathways (Israel et al, 2000). Recently, the proapoptotic activity of TOS has been linked to its ability to induce the accumulation of reactive oxygen species (Kang et al, 2004;Dong et al, 2008), leading to mitochondrial destabilization (Neuzil et al, 2007). TOS-induced apoptosis appears to be mediated by caspase activation in majority of cancer cell lines, although the contribution of caspase 9 or caspase 8 differs depending on the cellular context (Swettenham et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

α-Tocopheryl succinate potentiates the paclitaxel-induced apoptosis through enforced caspase 8 activation in human H460 lung cancer cells

et al. 2009

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Paclitaxel is one of the chemotheraputic drugs widely used for the treatment of nonsmall cell lung cancer (NSCLC) patients. Here, we tested the ability of α-tocopheryl succinate (TOS), another promising anticancer agent, to enhance the paclitaxel response in NSCLC cells. We found that sub-apoptotic doses of TOS greatly enhanced paclitaxel-induced growth suppression and apoptosis in the human H460 NSCLC cell lines. Our data revealed that this was accounted for primarily by an augmented cleavage of poly(ADP-ribose) polymerase (PARP) and enhanced activation of caspase-8. Pretreatment with z-VAD-FMK (a pan-caspase inhibitor) or z-IETD-FMK (a caspase-8 inhibitor) blocked TOS/paclitaxel cotreatment-induced PARP cleavage and apoptosis, suggesting that TOS potentiates the paclitaxel-induced apoptosis through enforced caspase 8 activation in H460 cells. Furthermore, the growth suppression effect of TOS/paclitaxel combination on human H460, A549 and H358 NSCLC cell lines were synergistic. Our observations indicate that combination of paclitaxel and TOS may offer a novel therapeutic strategy for improving paclitaxel drug efficacy in NSCLC patient therapy as well as for potentially lowering the toxic side effects of paclitaxel through reduced drug dosage.

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Vitamin E analogues as a novel group of mitocans: Anti-cancer agents that act by targeting mitochondria

Cited by 99 publications

References 202 publications

Suppression of Tumor GrowthIn vivoby the Mitocan α-tocopheryl Succinate Requires Respiratory Complex II

Suppression of Tumor GrowthIn vivoby the Mitocan α-tocopheryl Succinate Requires Respiratory Complex II

Effect of RRR-α-tocopherol succinate on the meat quality and antioxidative status in broilers

α-Tocopheryl succinate potentiates the paclitaxel-induced apoptosis through enforced caspase 8 activation in human H460 lung cancer cells

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