α-Tocopheryl succinate induces apoptosis in erbB2-expressing breast cancer cell via NF-κB pathway

Xiu-fang, Wang; Xie, Ying; Wang, Honggang; Zhang, Yuan; Duan, Xiaocui; Lu, Zhanjun

doi:10.1038/aps.2010.171

Cited by 21 publications

(19 citation statements)

References 27 publications

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“…We anticipated this to be the case since the ether form of the agent would be expected to be more stable (therefore exerting longer half‐life) in the circulation of the experimental animal than the ester α‐TOS, a paradigm documented earlier for another ether analog, α‐tocopheryloxybutyric acid 37. Further, we showed before that α‐TOS efficiently kills cultured HER2‐positive breast cancer cells by causing mitochondria‐dependent apoptosis 17…”

Section: Resultsmentioning

confidence: 91%

“…We and others have been developing novel anti‐cancer drugs from the group of vitamin E (VE), epitomized by the redox‐silent α‐tocopheryl succinate (α‐TOS) 11–15. These agents have been shown to be efficient against a range of cancer types,16 including HER2‐positive breast tumors, as documented in studies with α‐TOS and breast cancer cell lines with high level of HER2 as well as transgenic mice with spontaneous HER2‐positive carcinomas 17, 18…”

mentioning

confidence: 99%

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α‐Tocopheryloxyacetic acid is superior to α‐tocopheryl succinate in suppressing HER2‐high breast carcinomas due to its higher stability

Dong

Grant

Massa

et al. 2012

Intl Journal of Cancer

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Breast cancer is the number one neoplastic disease of women, with the HER2-high carcinomas presenting a considerable challenge for efficient treatment. Therefore, a search for novel agents active against this type of cancer is warranted. We tested two vitamin E (VE) analogs, the esterase-hydrolyzable a-tocopheryl succinate (a-TOS) and the non-hydrolyzable ether a-tocopheryloxyacetic acid (a-TEA) for their effects on HER2-positive breast carcinomas using a breast tumor mouse model and breast cancer cell lines. Ultrasound imaging documented that a-TEA suppressed breast carcinomas in the transgenic animals more efficiently than found for its ester counterpart. However, both agents exerted a comparable apoptotic effect on the NeuTL breast cancer cells derived from the FVB/N c-neu mice as well as in the human MBA-MD-453 and MCF7 HER2-18 cells with high level of HER2. The superior anti-tumor effect of a-TEA over a-TOS in vivo can be explained by longer persistence of the former in mice, possibly due to the enhanced plasma and hepatic processing of a-TOS in comparison to the esterase-non-cleavable a-TEA. Indeed, the stability of a-TOS in plasma was inferior to that of a-TEA. We propose that a-TEA is a promising drug efficient against breast cancer, as documented by its effect on experimental HER2-positive breast carcinomas that present a considerable problem in cancer management.Breast cancer is a neoplastic disease with very high incidence in women, with a current prediction that one of eight females will develop breast cancer during their lifespan and the trend appears grim.1 Up to 30% of breast cancers can be characterized by high level expression of the receptor tyrosine kinase erbB2 (HER2), which seriously complicates the treatment of such neoplasias due to enhanced proliferative status and resistance to apoptosis.2-4 The most frequently used therapeutics for HER2-positive breast cancer is the humanized antibody Herceptin (trastuzumab), often in combination with chemotherapeutic agents.5 Although this approach has been applied with some success, Herceptin is a serious economical burden and, more importantly, exerts severe cardiotoxic side-effects. 6,7 Mitocans, drugs with anti-cancer activity acting via mitochondrial destabilization, often causing early generation of reactive oxygen species (ROS), have been a recent focus of research. [8][9][10] We and others have been developing novel anticancer drugs from the group of vitamin E (VE), epitomized by the redox-silent a-tocopheryl succinate (a-TOS). 11-15These agents have been shown to be efficient against a range of cancer types, 16 including HER2-positive breast tumors, as documented in studies with a-TOS and breast cancer cell lines with high level of HER2 as well as transgenic mice with spontaneous HER2-positive carcinomas. 17,18 One problem with esters like a-TOS is that they are vulnerable to esterases, 19 making their stability/retention in the system relatively low, potentially jeopardizing their clinical application. This problem may be potentially overcome...

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Section: Resultsmentioning

confidence: 91%

mentioning

confidence: 99%

α‐Tocopheryloxyacetic acid is superior to α‐tocopheryl succinate in suppressing HER2‐high breast carcinomas due to its higher stability

Dong

Grant

Massa

et al. 2012

Intl Journal of Cancer

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“…Next, we evaluate if this immediate effect on Dc could be explained by the a-TOS action on AKT and NFkB signaling, as these pathways had been described as targets. 23 a-TOS did not affect NFkB activation by TNFa (Figure 2d) and its effect in AKT activation happened only after 15 min stimulation, in fact after 45 min of exposure to the drug (Figure 2e). …”

Section: A-tos Induced An Immediate Dissipation Of Mitochondrial Membmentioning

confidence: 92%

(+)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

et al. 2011

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The vitamin E derivative (þ)a-tocopheryl succinate (a-TOS) exerts pro-apoptotic effects in a wide range of tumors and is well tolerated by normal tissues. Previous studies point to a mitochondrial involvement in the action mechanism; however, the early steps have not been fully elucidated. In a model of acute promyelocytic leukemia (APL) derived from hCG-PML-RARa transgenic mice, we demonstrated that a-TOS is as effective as arsenic trioxide or all-trans retinoic acid, the current gold standards of therapy. We also demonstrated that a-TOS induces an early dissipation of the mitochondrial membrane potential in APL cells and studies with isolated mitochondria revealed that this action may result from the inhibition of mitochondrial respiratory chain complex I. Moreover, a-TOS promoted accumulation of reactive oxygen species hours before mitochondrial cytochrome c release and caspases activation. Therefore, an in vivo antileukemic action and a novel mitochondrial target were revealed for a-TOS, as well as mitochondrial respiratory complex I was highlighted as potential target for anticancer therapy.

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“…The amide analogues, such as a-tocopheryl maleyl amide (a-TAM), are very potent inducers of apoptosis in a number of cancer cell lines, including the erbB2-over-expressing breast cancer cells [23], as well as lymphoma and neuroblastoma cells [65,66]. However, a-TAM was found extremely toxic in vivo, when injected into the peritoneum of mice as a free compound.…”

Section: Other Proapoptotic Analogues Of Vitamin Ementioning

confidence: 99%

“…The redox-silent analogues of vitamin E belong to one of seven groups of mitocans [18][19][20]. a-Tocopheryl succinate (a-TOS), representative of these analogues, selectively induces apoptosis in a variety of types of malignant cells through mitochondria-dependent apoptotic signalling [21][22][23][24]. Mitochondrial DNA-deficient cells (q 0 phenotype) are resistant to a-TOS compared with their parental cells [22,23], indicating that mitochondria are key signalling transmitters of apoptosis induced by this ester analogue of vitamin E.…”

Section: Introductionmentioning

confidence: 99%

Vitamin E analogues as mitochondria‐targeting compounds: From the bench to the bedside?

Zhao

Neužil

Wu³

2008

Molecular Nutrition Food Res

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Despite considerable effort focusing on designing and finding efficient anti-cancer drugs over the last decade, little progress has been achieved, in particular in case of highly recalcitrant malignancies. Also, since there is a trend suggesting that deaths from cancers may be more frequent than from cardiovascular diseases, it is important to look for novel efficient and selective therapeutic approaches to gradually start winning the battle with cancer. Redox-silent vitamin E analogues, epitomised by alpha-tocopheryl succinate, give some hope in the quest for drugs with such properties. Thus far, these agents have been successfully tested in experimental animals with different types of cancer, showing high efficacy against malignancies including HER2-positive breast carcinomas or malignant mesotheliomas. Further research will provide additional, necessary data to launch clinical trials, possibly in near future, translating into development of innovative anti-cancer drugs acting by targeting mitochondria selectively in cancer cells.

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α-Tocopheryl succinate induces apoptosis in erbB2-expressing breast cancer cell via NF-κB pathway

Cited by 21 publications

References 27 publications

α‐Tocopheryloxyacetic acid is superior to α‐tocopheryl succinate in suppressing HER2‐high breast carcinomas due to its higher stability

α‐Tocopheryloxyacetic acid is superior to α‐tocopheryl succinate in suppressing HER2‐high breast carcinomas due to its higher stability

(+)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

Vitamin E analogues as mitochondria‐targeting compounds: From the bench to the bedside?

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