Vitamin E analogues as inducers of apoptosis: structure–function relation

Birringer, Marc; Eytina, John; Salvatore, Brian A.; Neužil, Jiřı́

doi:10.1038/sj.bjc.6600981

Cited by 128 publications

(125 citation statements)

References 26 publications

(32 reference statements)

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“…Thus, a-TOS, although also acting via the JNK pathway (Yu et al, 2001) signalling downstream through Bax (Lei et al, 2002), promotes the receptor-dependent pathway, thereby maximizing the apoptotic potential of the cell. In conclusion, our data show that a-TOS efficiently potentiates TRAIL killing of MM cells that are highly resistant to established treatment via mitochondrial mechanisms, and prompt testing of TRAIL and a-TOS, as well as other vitamin E analogues (Birringer et al, 2003), in preclinical models of MM. The potential combinatorial clinical use of a-TOS and TRAIL is supported by our recent findings that the vitamin E analogue promotes survival of immunocompromised mice with experimental peritoneal mesothelioma (Tomasetti et al, in press).…”

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confidence: 65%

α-Tocopheryl succinate and TRAIL selectively synergise in induction of apoptosis in human malignant mesothelioma cells

Tomasetti¹,

Rippo²,

Alleva

et al. 2004

Br J Cancer

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Malignant mesothelioma (MM) is a fatal type of neoplasia with poor therapeutic prognosis, largely due to resistance to apoptosis. We investigated the apoptotic effect of a-tocopheryl succinate (a-TOS), a strong proapoptotic agent, in combination with the immunological apoptogen TNF-related apoptosis-inducing ligand (TRAIL) on both MM and nonmalignant mesothelial cells, since MM cells show low susceptibility to the clinically intriguing TRAIL. All MM cell lines tested were sensitive to a-TOS-induced apoptosis, and exerted high sensitivity to TRAIL in the presence of subapoptotic doses of the vitamin E analogue. Neither TRAIL or a-TOS alone or in combination caused apoptosis in nonmalignant mesothelial cells. Isobologram analysis of the cytotoxicity assays revealed a synergistic interaction between the two agents in MM cells and their antagonistic effect in nonmalignant mesothelial cells. TRAILinduced apoptosis and its augmentation by a-TOS were inhibited by the caspase-8 inhibitor Z-IETD-FMK and the pan-caspase inhibitor Z-VAD-FMK. Activation of caspase-8 was required to induce apoptosis, which was amplified by a-TOS via cytochrome c release following Bid cleavage, with ensuing activation of caspase-9. Enhancement of TRAIL-induced apoptosis in MM cells by a-TOS was also associated with upregulation of the TRAIL cognate death receptors DR4 and DR5. Our results show that a-TOS and TRAIL act in synergism to kill MM cells via mitochondrial pathway, and are nontoxic to nonmalignant mesothelial cells. These findings are indicative of a novel strategy for treatment of thus far fatal MM.

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confidence: 65%

α-Tocopheryl succinate and TRAIL selectively synergise in induction of apoptosis in human malignant mesothelioma cells

Tomasetti¹,

Rippo²,

Alleva

et al. 2004

Br J Cancer

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“…18 A recent report suggested that apoptosis inducers, which are weak acids, are selectively taken up by malignant cells due to the acidic interstitium of the tumor, 44 so the addition of a chargeable group on the aromatic ring of T may contribute to the selectivity of TS against cancer cells. If, as might be expected in analogy to TS, the addition of a chargeable group to T3 enhances the selectivity of the agent to malignant cells, T3E may be established as a new cancer agent.…”

Section: Discussionmentioning

confidence: 99%

“…On the contrary, T succinate (TS), an ester derivative and a non-antioxidant form of T, is a potent growth inhibitor against cancer cells in vitro. 17 Moreover, the cytotoxicity of ␥-tocotrienol, a family of tocotrienols, against cancer cells in vitro has been enhanced by blocking its antioxidant property according to the same procedure with T. 18 This method seems to be effective to block the antioxidant property of tocotrienols. However, the anti-apoptotic activity of TS has been abrogated in cells that can hydrolyze the ester bond of TS and convert to T. 19 To overcome the disadvantage of the above strategy to block the antioxidant property in vivo, it may be useful to block the antioxidant activity of tocotrienols through the ether bond but not the ester bond, because the ether bond can not be hydrolyzed by enzymes such as esterase.…”

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confidence: 99%

Induction of cytotoxicity in human lung adenocarcinoma cells by 6‐O‐carboxypropyl‐α‐tocotrienol, a redox‐silent derivative of α‐tocotrienol

Yano

Satoh

Fukumoto

et al. 2005

Intl Journal of Cancer

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Tocotrienols are one of the most potent anticancer agents of all natural compounds and the anticancer property may be related to the inactivation of Ras family molecules. The anticancer potential of tocotrienols, however, is weakened due to its short elimination half life in vivo. To overcome the disadvantage and reinforce the anticancer activity in tocotrienols, we synthesized a redox-silent analogue of ␣-tocotrienol (T3), 6-O-carboxypropyl-␣-tocotrienol (T3E). We estimated the possibility of T3E as a new anticancer agent against lung adenocarcinoma showing poor prognosis based on the mutation of ras gene. T3E showed cytotoxicity against A549 cells, a human lung adenocarcinoma cell line with a ras gene mutation, in a dose-dependent manner (0 -40 M), whereas T3 and a redox-silent analogue of ␣-tocopherol (T) Key words: ␣-tocotrienol; redox-silent derivative; lung adenocarcinoma; Ras; cytotoxicity; Bcl-xL; cyclin D Lung cancer, particularly non-small cell lung cancer (NSCLC), is one of the most common forms of cancer and is the leading cause of cancer death in the West. 1 NSCLC exhibiting adenocarcinoma histology forms the majority of lung cancers and its ras genes carry mutations. 2 Furthermore, the presence of mutated ras genes in lung adenocarcinoma is linked with shortened patient survival. 3 These reports indicate that signaling pathways activated by mutated Ras protein contribute to the appearance of malignant phenotypes in lung adenocarcinoma. Thus, the inhibition of the mutated Ras function may be a promising procedure to regulate the development of lung cancer.,Mutated Ras proteins remain locked in an active state, and for the activated proteins to transduce the signals into downstream molecules, the proteins must be associated with the inner surface of the plasma membrane. 4 The critical process for the attachment of Ras to the inner surface of the plasma membrane is farnesylation of the C-terminal in Ras protein. 5 Because the inhibition of farnesylation can prevent Ras from maturing into its biologically active form, the inhibition is considered a potential therapeutic procedure for current cancer therapy. 6,7 In general, tumors undergo deregulated cholesterogenesis mainly via the upregulation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a key enzyme of cholesterol synthesis. 8 HMG-CoA reductase plays a key role in controlling cell proliferation by generating prenyl intermediates, particularly farnesyl and geranyl-geranyl moieties, 8 so the upregulation of the enzyme in tumors finally stimulates the cell proliferation via the increase of prenylation in Ras molecules. Thus, agents such as lovastin, which had been exploited previously for lowering cholesterol based on the inhibition of HMG-CoA reductase, may be useful chemotherapeutic agents for treating tumors harboring oncogenic ras mutation. 8 Natural constituents such as sundry mevalonate-derived constituents (isoprenoids) of fruits, vegetables and cereal grains suppress the development of tumors, 9 and the suppressive effect mainly...

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“…Furthermore, tocopheryl succinate and even more tocopheryl maleate (12) or the non-hydrolysable ether analog of a-tocopherol, a-TEA (2,5,7,8-tetramethyl-2R-(4R, 8R-12-trimethyltridecyl) chroman-6-yloxyacetic acid) (13) have been shown to have cell properties far stronger than a-tocopherol. As working hypothesis it can be suggested that the nonhydrolysable tocopheryl succinate and tocopheryl maleate may mimic and substitute for TP causing a permanent activation of cellular signals.…”

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confidence: 99%

On the Existence of Cellular Tocopheryl Phosphate, its Synthesis, Degradation and Cellular Roles: A Hypothesis

Negis

Zingg

Ogru³

et al. 2005

IUBMB Life (International Union of Biochemistry and Molecular B

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The finding that a-tocopheryl phosphate is present in cells in small amounts, that it can be synthesized and hydrolyzed supports the hypothesis that a-tocopheryl phosphate might be a signaling molecule. The possible pathways needed for the synthesis, hydrolysis and signaling are considered in this hypothesis as well the possible extension of this reaction to additional molecules such as tocopherols and tocotrienols. A possible mechanism of action of other tocopherol esters (succinate and maleate) is also hypothesized.

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Vitamin E analogues as inducers of apoptosis: structure–function relation

Cited by 128 publications

References 26 publications

α-Tocopheryl succinate and TRAIL selectively synergise in induction of apoptosis in human malignant mesothelioma cells

α-Tocopheryl succinate and TRAIL selectively synergise in induction of apoptosis in human malignant mesothelioma cells

Induction of cytotoxicity in human lung adenocarcinoma cells by 6‐O‐carboxypropyl‐α‐tocotrienol, a redox‐silent derivative of α‐tocotrienol

On the Existence of Cellular Tocopheryl Phosphate, its Synthesis, Degradation and Cellular Roles: A Hypothesis

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