QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kline, K. Articles by Sanders, B. G. Search for Related Content PubMed PubMed Citation Articles by Kline, K. Articles by Sanders, B. G.

---

Supplement: International Research Conference on Food, Nutrition, and Cancer

Vitamin E and Breast Cancer¹

Division of Nutrition and School of Biological Sciences, University of Texas at Austin, Austin, TX 78712

²To whom correspondence should be addressed. E-mail: k.kline{at}mail.utexas.edu.

	ABSTRACT

TOP ABSTRACT LITERATURE CITED

 
Vitamin E is a term that describes a group of compounds with similar yet unique chemical structures and biological activities. One interesting property possessed by certain vitamin E compounds—namely, -tocotrienol, RRR--tocopheryl succinate [vitamin E succinate (VES), a hydrolyzable ester-linked succinic acid analogue of RRR--tocopherol], and a novel vitamin E analogue referred to as -TEA (-tocopherol ether linked acetic acid analogue, which is a stable nonhydrolyzable analogue of RRR--tocopherol)—is their ability to induce cancer cells but not normal cells to undergo a form of cell death called apoptosis. In contrast, the parent compound, RRR--tocopherol, also referred to as natural or authentic vitamin E and known for its antioxidant properties, does not induce cancer-cell apoptosis. Efforts to understand how select vitamin E forms can induce cancer cells to undergo apoptosis have identified several nonantioxidant biological functions, including restoration of pro-death transforming growth factor-ß and Fas signaling pathways. Recent studies with -TEA show it to be a potent inducer of apoptosis in a wide variety of epithelial cancer cell types, including breast, prostate, lung, colon, ovarian, cervical, and endometrial in cell culture, and to be effective in significantly reducing tumor burden and metastasis in a syngeneic mouse mammary tumor model, as well as xenografts of human breast cancer cells. Studies also show that -TEA, in combination with the cyclooxygenase-2 inhibitor celecoxib and the chemotherapeutic drug 9-nitro-camptothecin decreases breast cancer animal model tumor burden and inhibits metastasis significantly better than do single-agent treatments.

KEY WORDS: • vitamin E • cancer • chemotherapy • tumor burden • metastasis

Vitamin E is a general term used indiscriminately to refer to a group of 8 different naturally occurring compounds known as tocopherols and tocotrienols, as well as synthetic vitamin E (a chemical mixture composed of 12.5% authentic RRR--tocopherol and 87.5% stereoisomers; namely, 7 molecules produced during the manufacturing process that have the same number and types of atoms found in RRR--tocopherol linked in the same order but differing in their spatial arrangement) (1,2). Thus, natural authentic vitamin E (referred to as RRR--tocopherol or d--tocopherol) and synthetic vitamin E (referred to as all-rac[emic]--tocopherol or dl--tocopherol) are not chemically equivalent (Fig. 1). RRR--tocopherol, the most prevalent form in the human body, has traditionally been recognized as a free radical-scavenging antioxidant important for protecting polyunsaturated fats from peroxidation, whose deficiency impairs mammalian fertility (1). Research suggesting that certain forms of vitamin E exhibit key nonantioxidant functions and data showing RRR--tocopherol to be selectively incorporated into the body over other biologically active vitamin E forms requires reevaluation of the role of vitamin E in health and disease processes (3–8).

View larger version (22K): [in this window] [in a new window]   FIGURE 1 Chemical structures of natural vitamin E (RRR--tocopherol), synthetic vitamin E (all-rac--tocopherol; a mixture of approximately equal amounts of 8 stereoisomers, only one of which is identical to natural vitamin E), and 2 analogs of natural vitamin E: -TEA (the RRR--tocopherol parent compound with a stable nonhydrolyzable ether-linked acetic acid moiety rather than an OH moiety at the C6 carbon) and VES (vitamin E succinate, which is the RRR--tocopherol parent compound with a hydrolyzable ester-linked succinic acid moiety rather than the OH moiety at the C6 carbon).

Recently, our laboratory developed a nonhydrolyzable ether analogue of RRR--tocopherol, referred to as -TEA³ (Fig. 1). -TEA is made from RRR--tocopherol by attaching an acetic acid moiety to the phenolic oxygen at carbon 6 of the chroman head by a nonhydrolyzable ether linkage. -TEA differs from the succinate and acetate derivatives not only in the attached moiety but also in the linkage; namely, a nonhydrolyzable ether linkage vs. a hydrolyzable ester linkage for the succinic acid and acetate forms (9). Thus, no antioxidant properties are expected for the intact -TEA analogue. Both vitamin E succinate (VES) and -TEA have been demonstrated to exhibit anticancer properties (2,9–15).

Despite intense study and great advances, causes, effective treatments, and prevention of cancers remain elusive. Deaths from cancer in both males and females is second only to deaths from heart disease (16). Breast and prostate cancers are the cancers with highest incidence in females and males, and these cancers are second only to lung cancer in causing death (16). Resistance to therapy is a hallmark of advanced cancers.

Cancers are clonal in origin, originating from normal cells that undergo multiple genetic changes, rendering survival advantage. Despite the enormous complexities involved in the conversion of normal cells to cancer cells, selection for survival appears to be a common event among cancers. Evolving cancer cells do not seem to follow one set pattern; rather, cancer development is a multistep process favoring genetic modifications that confer cell survival. Advanced cancers that acquire growth factor independence and resistance to apoptosis exhibit further survival advantage (17). Studies in our laboratory show that the acquisition of resistance to apoptosis by breast, ovarian, and prostate cancer cells are reversible events, with vitamin E compounds -TEA and VES inducing the cancer cells to undergo cell death by restoration of pro-death signaling pathways (10,15,18–22).

The role of diet and nutrition in cancer prevention and treatment was extensively covered at the American Institute for Cancer Research Conference on Food, Nutrition, and Cancer in 2003 (23,24). Specific nutrients and dietary constituents are known to be important players in cancer prevention and treatment (25,26). It is becoming increasingly clear that treatment of aggressive cancers that have metastasized to distant secondary sites is a daunting task, and expectations that a single agent will eliminate such cancers are not realistic. The focus of our studies is on vitamin E induced cell death by apoptosis of human breast cancer cells via restoration of pro-death signaling pathways.

Objectives of this review are to summarize what is currently known about 1) the potential of vitamin E as a chemopreventive agent; 2) the efficacy of the vitamin E derivative -TEA, alone and in combination with established therapeutic drugs, as an anticancer agent for reduction of tumor burden and metastasis, using a syngeneic murine mammary cancer model as well as a human xenograft model involving human breast cancer cells; and 3) mechanisms of action of vitamin E compounds in tumor burden reduction and inhibition of metastasis.

Vitamin E chemopreventive potential

Although vitamin E is a popular supplement marketed for its potential beneficial antioxidant effects for a number of chronic diseases, including various forms of cancer, a Food and Nutrition Board panel on Dietary Reference Intakes for vitamin C, vitamin E, selenium, and carotenoids concluded that observational epidemiological studies provide only limited evidence for a protective association of vitamin E with lung cancer (1). Furthermore, the Food and Nutrition Broad concluded that data from randomized clinical trials, which are considered the gold standard for health research, are suggestive for the ability of vitamin E to prevent prostate cancer but caution that this information is from a single trial that needs to be confirmed and that this study was not designed to examine the correlation between vitamin E and prostate cancer (1).

Two extensive reviews of epidemiologic studies (observational studies and intervention trials) investigating various relationships between vitamin E and breast cancer, including vitamin E dietary intake, vitamin E serum levels, or -tocopherol levels in subcutaneous adipose tissue, were published recently (27,28). Schwenke (28) concluded that observational studies that analyzed dietary exposure to RRR--tocopherol with or without the presence of other tocopherols or tocotrienols suggests that vitamin E from dietary sources may modestly protect women from breast cancer; however, there was no evidence that vitamin E supplements conferred any protection against breast cancer. The popular antioxidant hypothesis proposes that antioxidant nutrients protect against chronic diseases by decreasing oxidative damage. However, this hypothesis has neither been proven nor consistently supported by the findings of published intervention trials (29).

Preventive studies using chemically induced mammary cancer in Sprague Dawley rats and dietary supplementation of vitamin E-adequate diets with various forms of vitamin E concluded that there was only limited or no evidence for a protective effect (2,27,28,30).

Compelling data to support natural vitamin E (RRR--tocopherol) as a chemopreventive agent are lacking. Preclinical data in the literature are inconclusive, and RRR--tocopherol failed to reduce the risk of cancer in large-scale clinical trials (1). Because RRR--tocopherol is preferentially taken up in the liver by binding to the -tocopherol transfer protein, this raises the question as to whether RRR--tocopherol may actually prevent the anticancer properties of other forms of vitamin E, perhaps by limiting their bioavailablity. Studies by Regina Brigelius-Flohe and co-workers (University of Potsdam, Germany, unpublished results, 2004) showed that uptake of RRR--tocopherol and RRR--tocopherol are at the same rate for the first 6 h after supplementation in humans but that -tocopherol is then rapidly metabolized. Studies in human ovarian A2780/cp70 cancer cells showed that both VES or -TEA are taken up by the tumor cells when administered in combination with RRR--tocopherol, but VES and -TEA levels in the cotreated cells are lower than in singly treated cells (12). These studies further showed that RRR--tocopherol alone did not induce the cells to undergo apoptosis and that combination treatments of RRR--tocopherol with either VES or -TEA resulted in decreased numbers of apoptotic cells in comparison to VES and -TEA treatments alone (12). In another study, compared with placebo control, supplementation of humans with 400 IU/d of RRR--tocopheryl acetate for 2 mo enhanced RRR--tocopherol serum levels by 32%, reduced serum RRR--tocopherol concentrations by 54%, and reduced detectable levels of RRR--tocopherol in individuals by 72% (31). This information, taken together with data that suggest that -tocopherol may be a more potent cancer chemopreventive agent than -tocopherol (32,33), along with the fact that vitamin E supplementation is common practice suggest that there is a potential for RRR--tocopherol interference with anticancer effectiveness of other vitamin E compounds, perhaps by limiting their bioavailability. This possibility deserves further investigation.

Development and evaluation of -TEA in rodent models as an anticancer agent

Approximately 50 vitamin E analogs were synthesized and screened for their ability to induce human tumor cells in culture to undergo apoptosis. Eleven vitamin E analogs exhibited potent anticancer properties, and -TEA was selected as the lead vitamin E compound for further development (Fig. 1). Because -TEA is a very hydrophobic compound, it was incorporated into liposomes to make it more water soluble. In addition to oral delivery, aerosol delivery was investigated, because this route has proved very effective for liposome-formulated compounds (9).

Liposome-formulated -TEA administered to BALB/c mice by aerosol (36 µg deposited into respiratory track daily) for 17 d significantly reduced subcutaneously injected 66 cl-4-GFP mouse mammary tumor cell growth and lung metastasis (9). Tumor volume was reduced by 65% in comparison with the aerosol control (P < 0.001). Aerosol and untreated controls exhibited 40% visible lung metastases; whereas mice treated with -TEA had no visible lung metastases (9). Lungs from aerosol control mice exhibited an average of 60 microscopic fluorescent green lung lesions, whereas mice treated with -TEA exhibited an average of 11 fluorescent microscopic lesions (9). In summary, these studies show -TEA to be an effective anticancer agent when used singly.

Liposome-formulated -TEA (36 µg deposited into respiratory track daily) or 9-nitro-camptothecin (9-NC; 0.4 µg deposited into respiratory track daily) administered to BALB/c mice by aerosol separately or in combination for 21 d reduced subcutaneously injected 66 cl-4-GFP mouse mammary tumor growth and lung metastasis (13). The combination of -TEA and 9-NC significantly reduced (P < 0.001) growth of tumors. The incidence of visible lung metastasis was 83% in control vs. 8% in the -TEA, 9-NC, and combination treated groups. Likewise, lungs and lymph nodes showed a statistically significant decrease in fluorescent microscopic lesions for the separate treatments, as well as the combination treatment. Analyses of primary tumor tissue for proliferation and apoptosis showed the separate and combination treatment groups to have lower numbers of proliferating cells and elevated numbers of apoptotic cells (13).

Liposome-formulated -TEA administered daily by aerosol (36 µg deposited into respiratory tract daily) and celecoxib administered daily by diet (500 or 1250 mg/kg), separately or in combination for 31 d reduced tumor growth of human MDA-MB-435 breast cancer cells transplanted into immune compromised NU/NU mice in comparison with control (P < 0.001 for all treatment groups) (14). The combination treatment of -TEA plus celecoxib (1250) reduced tumor volume significantly better than either single treatment (P < 0.001 and P < 0.001, respectively) (14). The mean number of visible lung metastases was significantly reduced in all treatment groups (except for the celecoxib 500 treatment group) in comparison with control (14). The mean number of fluorescent lung and lymph-node metastases in all treatment groups was significantly lower than in the control group. Furthermore, the mean number of microscopic lung metastases in the -TEA plus celecoxib (1250) group was significantly lower than for either separate treatment (14).

Taken together, these rodent model studies suggest that -TEA is an effective anticancer agent both alone and in combination with other established anticancer agents.

Mechanisms whereby -TEA and VES inhibit cancer

Our mechanistic studies have focused primarily on the mechanisms whereby VES inhibits the growth of human breast cancers in culture by induction of DNA synthesis arrest, cellular differentiation, and apoptosis (7,18,21,34,35). Inhibition of cell proliferation involves a G0/G1 cell-cycle block, mediated in part by mitogen-activated protein kinases MEK1 and ERK1 and upregulation of the key cell-cycle regulatory protein p21(waf1/cip1) (21). Induction of differentiation is characterized by morphological changes, elevated beta casein messenger RNA, expression of milk lipids, elevated cytokeratin 18 protein, and downregulation of Her2/neu protein expression (34). Differentiation is mediated in part by activation of MEK1, ERK1/2, and phosphorylation of the transcription factor c-Jun (35).

Of the multiple apoptotic signaling events modulated by VES, especially noteworthy are its ability to convert Fas/Fas ligand nonresponsive human breast cancer cells to Fas/Fas ligand responsiveness and to convert transforming growth factor-ß (TGF-ß) nonresponsive breast cancer cells to TGF-ß responsiveness, with both restored signaling pathways converging on prolonged activation of JNK/c-Jun, followed by translocation of Bax protein to the mitochondria, induction of mitochondria permeability transition, followed by cytochrome c release into the cytoplasm, activation of caspases 9 and 3, cleavage of poly (ADP-ribose) polymerase, and apoptosis (36). Although the mechanisms whereby -TEA induces human MDA-MB-435 breast cancer cells to undergo apoptosis have not been studied as extensively, studies thus far show -TEA to mimic VES. Treatment of MDA-MB-435 breast cancer cells with -TEA restores both Fas/Fas ligand and TGF-ß signaling pathways, which converge on JNK, followed by induction of apoptosis (15).

Summary

Vitamin E describes a number of compounds that differ in chemical structure and biological activity. Of the vitamin E forms, -tocopherol; -, -, and -tocotrienol; and derivatives VES and -TEA selectively induce cancer cells to undergo apoptosis. Although progress in characterizing the antitumor functions of vitamin E forms has been made, much remains to be done. Comparative analyses of individual vitamin E compounds, separately and in combination, in preclinical animal models deserve further investigation.

	FOOTNOTES

 
¹ Published in a supplement to The Journal of Nutrition. Presented as part of the International Research Conference on Food, Nutrition, and Cancer held in Washington, DC, July 15–16, 2004. This conference was organized by the American Institute for Cancer Research and the World Cancer Research Fund International and sponsored by BASF Aktiengesellschaft; Campbell Soup Company; The Cranberry Institute; Danisco USA Inc.; DSM Nutritional Products, Inc.; Hill’s Pet Nutrition, Inc.; Kellogg Company; National Fisheries Institute; The Solae Company; and United Soybean Board. An educational grant was provided by The Mushroom Council. Guest editors for this symposium were Helen A. Norman, Vay Liang W. Go, and Ritva R. Butrum.

³ Abbreviations used: -TEA, -tocopherol ether linked acetic acid analog; 9-NC, 9-nitro-camptothecin; TGF-ß, transforming growth factor-ß; VES, vitamin E succinate.

	LITERATURE CITED

TOP ABSTRACT LITERATURE CITED

 

1. Institute of Medicine, Food and Nutrition Board, Panel on Dietary Antioxidants and Related Compounds (2000) Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids 2000 National Academy Press Washington, DC.

2. Kline, K., Lawson, K. A., Yu, W. & Sanders, B. G. (2003) Vitamin E and breast cancer prevention: current status and future potential. J. Mammary Gland Biol. Neoplasia 8:91-102.[Medline]

3. Traber, M. G. & Packer, L. (1995) Vitamin E: beyond antioxidant function. Am. J. Clin. Nutr. 62:1501S-1509S.[Abstract/Free Full Text]

4. Brigelius-Flohe, R., Kelly, F. J., Salonen, J. T., Neuzil, J., Zingg, J.-M. & Azzi, A. (2002) The European perspective on vitamin E: current knowledge and future research. Am. J. Clin. Nutr. 76:703-716.[Abstract/Free Full Text]

5. Brigelius-Flohe, R. & Traber, M. G. (1999) Vitamin E: function and metabolism. FASEB J. 10:1145-1155.

6. Stocker, A. & Azzi, A. (2000) Tocopherol-binding proteins: their function and physiological significance. Antioxid. Redox Signal. 3:397-404.

7. Kline, K., Yu, W. & Sanders, B. G. (2001) Vitamin E: mechanisms of action as tumor cell growth inhibitors. J. Nutr. 131:161S-163S.[Free Full Text]

8. Ricciarelli, R., Zingg, J-M. & Azzi, A. (2002) The 80th anniversary of vitamin E: beyond its antioxidant properties. Biol. Chem. 383:457-465.[Medline]

9. Lawson, K. A., Anderson, K., Menchaca, M., Atkinson, J., Sun, L.-Z., Knight, V., Gilbert, B. E., Conti, C., Sanders, B. G. & Kline, K. (2003) Novel vitamin E analogue decreases syngeneic mouse mammary tumor burden and reduces lung metastasis. Mol. Cancer Ther. 2:437-444.[Abstract/Free Full Text]

10. Neuzil, J., Kagedal, K., Andera, L., Weber, C. & Brunk, U. T. (2002) Vitamin E analogs: a new class of multiple action agents with anti-neoplastic and anti-atherogenic activity. Apoptosis 7:179-187.[Medline]

11. Neuzil, J., Weber, T., Terman, A., Weber, C. & Brunk, U. T. (2001) Vitamin E analogues as inducers of apoptosis: implications for their potential antineoplastic role. Redox. Rep. 6:143-151.[Medline]

12. Anderson, K., Simmons-Menchaca, M., Lawson, K. A., Atkinson, J., Sanders, B. G. & Kline, K. (2004) Differential response of human ovarian cancer cells to induction of apoptosis by vitamin E succinate and vitamin E analogue, -TEA. Cancer Res. 64:4263-4269.[Abstract/Free Full Text]

13. Lawson, K. A., Anderson, K., Snyder, R. M., Simmons-Menchaca, M., Atkinson, J., Sun, L.-Z., Bandyopadhyay, A., Knight, V. & Gilbert, B. E., et al (2004) Novel vitamin E analogue and 9-nitro-camptothecin administered as liposome aerosols decrease syngeneic mouse mammary tumor burden and inhibit metastasis. Cancer Chemotherap. Pharmacol. (in press).

14. Zhang, S., Lawson, K. A., Simmons-Menchaca, M., Sun, L.-Z., Sanders, B. G. & Kline, K. (2004) Vitamin E analog -TEA and celecoxib alone and together reduce human MDA-MB-435-FL-GFP breast cancer burden and metastasis in nude mice. Breast Cancer Res. Treat. 87:111-121.[Medline]

15. Shun, M.-C., Yu, W., Gapor, A., Parsons, R., Atkinson, J., Sanders, B. G. & Kline, K. (2004) Pro-apoptotic mechanisms of action of a novel vitamin E analog (-TEA) and a naturally occurring form of vitamin E (-tocotrienol) in MDA-MB-435 human breast cancer cells. Nutr. Cancer 48:95-105.[Medline]

16. Jemal, A., Tiwari, R. C., Murray, T., Ghafoor, A., Samuels, A., Ward, E., Feuer, E. J. & Thun, M. J. (2004) Cancer statistics, 2004. CA Cancer J. Clin. 54:8-29.[Abstract/Free Full Text]

17. Boyd, D. B. (2003) Insulin and cancer. Integr. Cancer Ther. 2:315-329.[Abstract]

18. Yu, W., Liao, Q. Y., Hantash, F. M., Sanders, B. G. & Kline, K. (2001) Activation of extracellular signal-regulated kinase and c-Jun-NH2-terminal kinase but not p38 mitogen-activated protein kinases is required for RRR--tocopheryl succinate-induced apoptosis of human breast cancer cells. Cancer Res. 61:6569-6576.[Abstract/Free Full Text]

19. Charpentier, A., Groves, S., Simmons-Menchaca, M., Turley, J., Zhao, B., Sander, B. G. & Kline, K. (1993) RRR--tocopheryl succinate inhibits proliferation and enhances secretion of transforming growth factor-ß (TGF-ß) by human breast cancer cells. Nutr. Cancer 19:225-239.[Medline]

20. Turley, J. M., Fu, T., Ruscetti, F. W., Mikovits, J. A., Bertolette, D. C. & Birchenall-Roberts, M. C. (1997) Vitamin E succinate induces Fas-mediated apoptosis in estrogen receptor-negative human breast cancer cells. Cancer Res. 57:881-890.[Abstract/Free Full Text]

21. Yu, W., Sanders, B. G. & Kline, K. (2002) RRR--tocopheryl succinate-induction of DNA synthesis arrest of human MDA-MB-435 cells involves TGF-ß independent activation of p21 (Waf1/Cip1). Nutr. Cancer 43:227-236.[Medline]

22. Yu, W., Israel, K., Liao, Q. Y., Aldaz, C. M., Sanders, B. G. & Kline, K. (1999) Vitamin E succinate (VES) induces Fas sensitivity in human breast cancer cells: role for Mr 43,000 Fas in VES-triggered appoptosis. Cancer Res. 59:953-961.[Abstract/Free Full Text]

23. Kritchevsky, D. (2003) Diet and cancer: What’s next?. J. Nutr. 133:3827S-3829S.[Abstract/Free Full Text]

24. Go, V.L.W., Butrum, R. R. & Wong, D. A. (2003) Diet, nutrition, and cancer prevention: The postgenomic era. J. Nutr. 133:3830S-3836S.[Abstract/Free Full Text]

25. Menach, C., Scalbert, A., Morand, C., Remesy, C. & Jimenez, L. (2004) Polyphenols: food sources and bioavailability. Am. J. Clin. Nutr. 79:727-747.[Abstract/Free Full Text]

26. Bingham, S. & Riboli, E. (2004) Diet and cancer—the European prospective investigation into cancer and nutrition. Nat. Rev. Cancer 4:206-215.[Medline]

27. Kimmick, G. G., Bell, R. A. & Bostick, R. M. (1997) Vitamin E and breast cancer: a review. Nutr. Cancer 27:109-117.[Medline]

28. Schwenke, D. C. (2002) Does lack of tocopherols and tocotrienols put women at increased risk of breast cancer?. J. Nutr. Biochem. 13:2-20.[Medline]

29. Stanner, S. A., Hughes, J., Kelly, C. N. & Buttriss, J. (2004) A review of the epidemiological evidence for the ’antioxidant hypothesis.’. Public Health Nutr. 7:407-422.[Medline]

30. Kelloff, G. J., Crowell, J. A., Boone, C. W., Steele, V. E., Lubet, R. A., Greenwald, P., Alberts, D. S., Covey, J. M. & Doody, L. A., et al (1994) Clinical development plans for cancer chemopreventive agents. J. Cell. Biochem. Suppl. 20:282-294.[Medline]

31. Huang, H. Y. & Appel, L. J. (2003) Supplementation of diets with alpha-tocopherol reduces serum concentrations of gamma- and delta-tocopherol in humans. J. Nutr. 133:3137-3140.[Abstract/Free Full Text]

32. Campbell, S., Stone, W., Whaley, S. & Krishnan, K. (2003) Development of gamma (gamma)-tocopherol as a colorectal cancer chemopreventive agent. Crit. Rev. Oncol. Hematol. 47:249-259.[Medline]

33. Hensley, K., Benaksas, E. J., Bolli, R., Comp, P., Grammas, P., Hamdheydari, L., Mou, S., Pye, Q. N. & Stoddard, M. F., et al (2004) New perspectives on vitamin E: gamma-tocopherol and carboxyelthylhydroxy-chroman metabolites in biology and medicine. Free Radic. Biol. Med. 36:1-15.[Medline]

34. You, H., Yu, W., Sanders, B. G. & Kline, K. (2001) RRR--tocopheryl succinate induces MDA-MB-435 and MCF-7 human breast cancer cells to undergo differentiation. Cell Growth Diff. 12:471-480.[Abstract/Free Full Text]

35. You, H., Yu, W., Munoz-Medellin, D., Brown, P. H., Sanders, B. G. & Kline, K. (2002) Role of extracellular signal-regulated kinase pathway in RRR--tocopheryl succinate-induced differentiation of human MDA-MB-435 breast cancer cells. Mol. Carcinog. 4:228-236.

36. Yu, W., Sanders, B. G. & Kline, K. (2003) RRR--tocopheryl succinate-induced apoptosis of human breast cancer cells involves Bax translocation to mitochondria. Cancer Res. 63:2483-2491.[Abstract/Free Full Text]

This article has been cited by other articles:

				Y. Cui, J. M Shikany, S. Liu, Y. Shagufta, and T. E Rohan Selected antioxidants and risk of hormone receptor-defined invasive breast cancers among postmenopausal women in the Women's Health Initiative Observational Study Am. J. Clinical Nutrition, April 1, 2008; 87(4): 1009 - 1018. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kline, K. Articles by Sanders, B. G. Search for Related Content PubMed PubMed Citation Articles by Kline, K. Articles by Sanders, B. G.