Induction of apoptosis in human breast cancer cells by tocopherols and tocotrienols

Yu, Weiping; Simmons‐Menchaca, Maria; Gapor, Abdul; Sanders, Bob G.; Kline, Kimberly

doi:10.1080/01635589909514744

Cited by 220 publications

(130 citation statements)

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“…More recent work has demonstrated that cell cycle inhibition by T3 occurs through the control of the Rb/cdk4/ cyclin D pathway (Elangovan et al 2008) that is also affected by the HM forms of tocopherols, and particularly by c-TOH (Betti et al 2006). In the same cell models, T3 were demonstrated to induce apoptosis with d-T3 as the most potent form (Yu et al 1999) and with a mechanism that involves mitochondrial disruption and cyt c release (Takahashi and Loo 2004). As introduced above, recent studies by our group confirmed that d-T3 is the most potent T3 form with pro-apoptotic activity higher than a-TOS in breast cancer cells (Table 1) .…”

Section: Metabolite Formation and Activitymentioning

confidence: 70%

Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E

et al. 2011

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The selective constraint of liver uptake and the sustained metabolism of tocotrienols (T3) demonstrate the need for a prompt detoxification of this class of lipophilic vitamers, and thus the potential for cytotoxic effects in hepatic and extra-hepatic tissues. Hypomethylated (c and d) forms of T3 show the highest in vitro and in vivo metabolism and are also the most potent natural xenobiotics of the entire vitamin E family of compounds. These stimulate a stress response with the induction of detoxification and antioxidant genes. Depending on the intensity of this response, these genes may confer cell protection or alternatively they stimulate a senescence-like phenotype with cell cycle inhibition or even mitochondrial toxicity and apoptosis. In cancer cells, the uptake rate and thus the cell content of these vitamers is again higher for the hypomethylated forms, and it is the critical factor that drives the dichotomy between protection and toxicity responses to different T3 forms and doses. These aspects suggest the potential for marked biological activity of hypomethylated ''highly metabolized'' T3 that may result in cytoprotection and cancer prevention or even chemotherapeutic effects. Cytotoxicity and metabolism of hypomethylated T3 have been extensively investigated in vitro using different cell model systems that will be discussed in this review paper as regard molecular mechanisms and possible relevance in cancer therapy.Keywords Tocotrienols Á Vitamin E Á Breast cancer Á Antioxidants Á Apoptosis Á Cell signaling Á Inflammation Á Metabolism Á Gene expression Á Cell redox T3 structure-function and specificity of actionIn the vitamin E family of molecules, tocotrienols (T3) are often considered of minor importance since these are less abundant than a and c tocopherol (TOH) in the circulation and in solid tissues. This has contributed to hinder our knowledge on the biological functions of this group of vitamers that is now regaining great interest, thanks to a number of recent studies that suggested health-promoting functions related with the cholesterol-lowering, cytoprotective, and anticarcinogenic effects of T3 [reviewed in (Aggarwal et al. (2010)].Structure-function studies demonstrate that many of these functions are more potent when the unsaturated (isoprenyl) side chain of T3 is combined with a hypomethylated (HM) chroman ring. The unsaturated chain characteristic of all the T3 forms confers well-defined physical and chemical characteristics that appear to include vitamer-specific interactions with other lipids and cell proteins (Atkinson

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Section: Metabolite Formation and Activitymentioning

confidence: 70%

Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E

et al. 2011

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“…However, polyunsaturated forms of VE may exert proapoptotic activity even with the redox-active hydroxyl group present. This is the case of g-T3H, which, unlike a-T3H, causes apoptosis in a variety of malignant cells (Yu et al, 1999;this report). An even stronger proapoptotic effect was observed for g-T2H, a homologue of g-T3H with the phenyl chain shorter by one isoprenyl unit.…”

Section: Resultsmentioning

confidence: 88%

Section: Resultsmentioning

confidence: 99%

“…Its desaturation, in the case of a-TOH, gives the naturally occurring a-T3H, which is nonapoptotic (Yu et al, 1999). g-T3H, however, has a strong apoptogenic activity (Yu et al, 1999), which is further enhanced by its conversion to g-T3S (Figure 6). Interestingly, a derivative of g-T3H with the aliphatic side chain shorter by one isoprenyl unit, a-T2H, exerted higher proapoptotic activity than did g-T3H itself (Figure 6).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2003

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Recent results show that a-tocopheryl succinate (a-TOS) is a proapoptotic agent with antineoplastic activity. As modifications of the vitamin E (VE) molecule may affect its apoptogenic activity, we tested a number of newly synthesised VE analogues using malignant cell lines. Analogues of a-TOS with lower number of methyl substitutions on the aromatic ring were less active than a-TOS. Replacement of the succinyl group with a maleyl group greatly enhanced the activity, while it was lower for the glutaryl esters. Methylation of the free succinyl carboxyl group on a-TOS and d-TOS completely prevented the apoptogenic activity of the parent compounds. Both Trolox and its succinylated derivative were inactive. a-tocotrienol (a-T3 H) failed to induce apoptosis, while g-T3 H was apoptogenic, and more so when succinylated. Shortening the aliphatic side chain of g-T3 by one isoprenyl unit increased its activity. Neither phytyl nor oleyl succinate caused apoptosis. These findings show that modifications of different functional moieties of the VE molecule can enhance apoptogenic activity. It is hoped that these observations will lead to the synthesis of analogues with even higher apoptogenic and, consequently, antineoplastic efficacy.

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“…Similar to tocopherols, the antiproliferative effects of tocotrienols are mediated by inhibition of protein kinase C [44]. In human and murine tumor cells, tocotrienols induce a cell-cycle arrest in the G-1 phase and apoptosis [54]. To the best of our knowledge, the potential of tocotrienols as antifibrotic agents has not been evaluated.…”

Section: Introductionmentioning

confidence: 96%

Tocotrienol inhibits proliferation of human Tenon’s fibroblasts in vitro: a comparative study with vitamin E forms and mitomycin C

Meyenberg

Goldblum

Zingg

et al. 2005

Graefe's Arch Clin Exp Ophthalmo

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Tocotrienol inhibits proliferation of human Tenon's fibroblasts in vitro: a comparative study with vitamin E forms and mitomycin C Abstract Purpose: To evaluate the potential of the vitamin E compound α-tocotrienol as antifibrotic agent in vitro. Methods: Using human Tenon's capsule fibroblast cultures, the antiproliferative and cytotoxic effects of the different vitamin E forms α-tocopherol, α-tocopheryl acetate, α-tocopheryl succinate and α-tocotrienol were compared with those of mitomycin C. To mimic subconjunctival and regular oral application in vivo, exposure time of serum-stimulated and serum-restimulated fibroblasts (SF and RF, respectively) to vitamin E forms was set at 6 days. Cultures were only exposed for 5 min to mitomycin C due to its known acute toxicity and to mimic the shorttime intraoperative administration. Proliferation (expressed as % of control) was determined by DNA content quantification on days 2, 4 and 6, whereas cytotoxicity was assessed by cell morphology and glucose 6-phosphate dehydrogenase (G6PD) release after 24 h. Results: α-Tocopherol and α-tocopheryl acetate stimulated growth of SF, but not RF. Reduction of fibroblast content by α-tocopheryl succinate was accompanied by increased G6PD release and necrosis. Contrary to α-tocopheryl succinate, 50 μM or repeatedly 20 μM of α-tocotrienol significantly inhibited proliferation without causing cellular toxicity (maximal effect: 46.8%). RF were more sensitive to this effect than SF. Mitomycin C 100-400 μg/ml showed a stronger antiproliferative effect than α-tocotrienol (maximal effect: 13.8%). Morphologic characteristics of apoptosis were more commonly found under treatment with mitomycin C. Conclusions: Of the vitamin E forms tested, only α-tocotrienol significantly inhibited growth at non-toxic concentrations. In this in vitro study, antiproliferative effects of mitomycin C were stronger than those of α-tocotrienol.

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Induction of apoptosis in human breast cancer cells by tocopherols and tocotrienols

Cited by 220 publications

References 28 publications

Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E

Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E

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

Tocotrienol inhibits proliferation of human Tenon’s fibroblasts in vitro: a comparative study with vitamin E forms and mitomycin C

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