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Vitamin E and Prostate Cancer: Is Vitamin E Succinate a Superior Chemopreventive Agent?

Posted on: Sunday, 24 July 2005, 03:00 CDT

There is convincing evidence that vitamin E succinate significantly reduces human prostate cancer growth in experimental models compared with α-tocopherol or tocopheryl acetate. Its intact delivery to cancer cells is questionable when administered orally; however, a study in transgenic mice showed a synergistic inhibitory effect of dietary vitamin E succinate, selenium, and lycopene on prostate cancer incidence. Clinical trials have yet to confirm this effect.

Key words: vitamin E succinate, selenium, synergy, apoptosis, prostate cancer

2005 International Life Sciences Institute

doi: 10.1301/nr.2005.jul.247-251

INTRODUCTION

Prostate cancer is the most common non-cutaneous cancer and is the second leading cause of cancer death in American men, exceeded only by lung cancer. In 2004, the American Cancer Society estimated that over 230,000 new prostate cancer cases would be diagnosed and that 29,900 deaths would occur from this disease.1 There is a close relationship between the occurrence of prostate cancer and the type of diet consumed by the population. Epidemiological studies have shown that in Asia, where the diet is low in animal fat and rich in soy protein, the incidence of prostate cancer is very low. Conversely, in industrialized western countries, where the diet is typically high in animal fat (30%-40% of calories from fat), the incidence of prostate cancer (and obesity) is concomitantly higher. Several studies have identified an association between various dietary substances with antioxidant properties and an inhibitory effect on the development and/or progression of prostate cancer.2 Dietary micronutrients such as carotenoids, lycopenes, retinoids, and vitamin A, vitamin E, vitamin C, selenium, and phenol- containing dietary substances have been shown to have effects that extend beyond their antioxidant properties.3

Vitamin E is a general term used to refer to a group of naturally occurring compounds called tocopherols and tocotrienols, as well as vitamin E derivatives such as acetate, succinate, and nicotinate of both natural and synthetic α-tocopherol.4 There have been relatively few in vivo studies on the effects of vitamin E on prostate cancer. This review summarizes the role of vitamin E in prostate cancer prevention and treatment and highlights the anti- neoplastic action of vitamin E succinate (VES).

VITAMIN E AND PROSTATE CANCER: ANIMAL STUDIES

Male Lady transgenic mice spontaneously develop localized prostate cancer and metastasis, which mimics the progression of human prostate cancer in many respects. In 2004, Venkateswaran et al.5 showed a significant reduction in prostate cancer incidence in male Lady transgenic mice fed a standard-fat (25% kcal from fat) or a high-fat (40% kcal from fat) diet with antioxidant supplementation compared with the controls. The anti-oxidant supplement included a daily dietary dose of a combination of 800 IU of VES, 200 g of seleno-dl-methionine, and 50 mg of lycopene. This was the first in vivo study showing the inhibitory effects of VES, in combination with selenium and lycopene, on the incidence of prostate cancer.

In this study,5 transgenic animals were divided into four main groups: group 1 animals were fed a standard (25% kcal from fat) diet; group 2 animals were fed a standard diet with antioxidant supplementation; group 3 animals were fed a high-fat (40% kcal from fat) diet; and group 4 animals were fed a high-fat diet with antioxidant supplementation. At the end of 28 to 32 weeks, the prostate tumor incidence was approximately 11% in group 2 and approximately 16% in group 4. This was a striking reduction compared with the controls, which had a tumor incidence of about 74% in group 1 and 100% in group 3. These investigators also measured the protein expression of cytoplasmic p27 and proliferating cell nuclear antigen (PCNA) in prostate tissue sections using immunohistochemistry. The tumor suppressor gene p27 is an important regulator of cell cycle progression from the G^sub 1^ to the S phase, and works by binding and inhibiting the cyclin E-/cyclin-dependent kinase 2 complex. PCNA serves as a critical marker for increased proliferation of DNA polymerase-driven DNA synthesis.5 Thus, both p27 and PCNA expression serve to elucidate possible mechanisms by which antioxidant supplementation could lead to a reduction in the incidence of prostate cancer. Venkateswaran et al.5 reported that PCNA expression was markedly reduced in prostate sections from both of the antioxidant-supplemented groups (groups 2 and 4) compared with the untreated controls, while p27 scoring was increased in the antioxidant-treated animals, which is consistent with a reduction in the incidence of prostate tumors.

Fleshner et al.6 previously reported an in vivo study using dietary supplementation of dl-α-tocopheryl acetate on the growth of human prostate LNCaP xenografts in nude mice. The human prostate LNCaP cell line (from lymph node metastasis) expresses androgen receptors and also produces prostate-specific antigen (PSA). Once implanted into nude mice, it undergoes local growth without metastases, making it well suited to studying tumor growth rates. In this study,6 following subcutaneous inoculation of the LNCaP cells, animals were randomly assigned to four groups: group 1 animals were fed a diet with 40% kcal from fat; group 2 animals were fed a diet with 40% kcal from fat supplemented with dl-a-tocopheryl acetate; group 3 animals were fed a diet with 20% kcal from fat; and group 4 animals were fed a diet with 20% kcal from fat supplemented with dl-α-tocopheryl acetate. The level of dl-α- tocopheryl acetate included in the diets of groups 2 and 4 was 11.4 IU/kg/d. This 15-week study revealed a significant reduction in LNCaP tumor size in group 2 compared with group 1. However, there was no significant difference between group 3 and group 4. Animals in group 1 had the highest tumor growth, and 50% of the animals in this group attained the target tumor size (0.1 cm^sup 3^) in 6 weeks. Tumor growth was significantly slower in group 2 animals and in the animals fed low-fat diets (groups 3 and 4) with or without vitamin E supplementation.

Both Venkateswaran et al.5 and Fleshner et al.6 reported in vivo data emphasizing the fact that a high-fat diet promotes the incidence and growth of prostate cancer, and that vitamin E alone (as dl-α-tocopheryl acetate) or in combination with other antioxidants (as VES plus selenium plus lycopene) ameliorates this high-fat-associated prostate cancer effect. Interestingly, Venkateswaran et al.5 reported a marked decrease in prostate cancer incidence even in the group fed the standard diet (25% kcal from fat) with antioxidant supplementation compared with the corresponding untreated controls, whereas Fleshner et al.6 showed no difference between the groups fed 20% kcal from fat, with or without vitamin E supplementation. This difference could be attributed to a different vitamin E derivative, a higher amount of vitamin E, or the longer period of vitamin E supplementation in the study reported by Venkateswaran et al.5 compared with Fleshner et al.6 (800 IU of VES/ d for 32 weeks versus 11.4 IU of dl-α-tocopheryl acetate/kg/d for 15 weeks, respectively).

VITAMIN E AND PROSTATE CANCER: IN VITRO STUDIES

According to Neuzil,7 when VES reaches the circulation, it binds to circulating lipoproteins that carry it to the microvasculature, where it kills the cancer cells. Lipoproteins with bound VES are cleared in the liver, where the hepatic nonspecific esterase cleaves the succinate moiety and the newly generated α-tocopherol is inserted by the a-tocopheryl-transfer protein into nascent very low- density lipoproteins, which are then circulated in the biological system. While normal cells, including intestinal epithelial cells, are capable of hydrolyzing VES to α-tocopherol, cancer cells lack this ability. As a result, accumulation of the intact VES molecule in cancer cells causes their apoptosis. In vitro studies have provided evidence of the inhibitory effects of a-tocopheryl succinate or VES on the growth of human prostate cancer cells. Venkateswaran et al.8 reported an overexpression of p27 and a dramatic reduction in the percentage of human prostate LNCaP and PC- 3 (from bone metastasis) cancer cells in the S phase in response to VES treatment over a 72-hour period. Thus, VES at a 20 g/mL (38 /L) concentration (IC^sub 50^ = 5 to 25 g/mL) caused a maximum reduction of cells replicating DNA. This concentration of VES used in the cell culture study is comparable to the physiological concentrations of tocopherol in human serum (30-40 mol/L). The results of this in vitro study on p27 induction by VES treatment8 are consistent with the in vivo study by the same group using VES in combination with selenium and lycopene.5 The mechanisms of VES action on human prostate cancer cells proposed by various investigators are numerous,9-13 and include distinct mechanisms that are listed in Table 1 and summarized in Figure 1.

Zu and Ip14 compared the anti-neoplastic action of α- tocopherol and its two ester derivatives, vitamin E acetate and VES, on the growth of human prostate PC-3 cells in culture. Interestingly, \a concentration of 20 M VES was sufficient to achieve a 40% growth inhibition of PC-3 cells after 72 hours of treatment, whereas neither α-tocopherol nor α-tocopheryl acetate was able to achieve the same after the same length of exposure and with a dose 10 times higher. Thus establishing the possible superiority of VES as a chemopreventive agent in prostate cancer prevention, Zu and Ip14 further investigated the effects of a combination of VES and selenium on PC-3 cells. Selenium exhibited anti-neoplastic effects similar to VES, resulting in cell cycle block, DNA synthesis suppression, and apoptosis induction. A combination of 2.5 M methylseleninic acid and 20 M VES produced a more effective apoptotic response than either agent alone after 72 hours of treatment.

Table 1. Summary of Proposed Mechanisms of Vitamin E Succinate Action on Human Prostate Cancer

Although in vivo studies with VES alone are lacking in the field of prostate cancer research, VES has shown dramatic results in the reduction of breast cancer xenografts in nude mice compared with controls. Malafa and Neitzel15 demonstrated that mice injected intraperitoneally with VES had significantly lower final tumor weights (0.043 g) compared with the control vehicle-treated group (0.116 g), whereas no difference was noted between mice treated subcutaneously with VES (0.090 g) and the control subcutaneously treated group (0.071 g). Thus, the route of VES administration has a profound effect on its antitumor activity in vivo. This effect remains to be established in prostate cancer growth in vivo, and may produce a similar or even greater inhibitory effect than that reported with oral ingestion of VES by Venkateswaran et al.5

VITAMIN E AND PROSTATE CANCER: HUMAN STUDIES

Possible synergy between vitamin E and selenium was the basis for the initiation of a large clinical trial on prostate cancer prevention by the National Cancer Institute. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was designed to test the hypothesis that selenium and vitamin E alone or in combination can reduce the clinical incidence of prostate cancer in a population- based cohort of men at risk. This clinical trial, started in 2001, randomized 32,400 healthy men with normal digital rectal examination and serum PSA to one of four study arms: selenium (as 200 g of L- selenomethionine) plus placebo; vitamin E (400 mg of racemic α- tocopheryl acetate, d- and 1- isomers) plus placebo; selenium plus vitamin E; or placebo plus placebo. Study agents will be taken orally for a minimum of 7 and a maximum of 12 years, with assessment of general health, incident prostate cancer, and toxicity performed at 12-month intervals.

The primary end point for SELECT is the clinical incidence of prostate cancer as determined by a recommended routine clinical diagnostic workup, including yearly digital rectal examination and serum PSA level. Prostate biopsy will be performed at the discretion of study physicians according to local community standards. Secondary end points will include prostate cancerfree survival, all- cause mortality, and the incidence and mortality of other cancers (e.g., lung and colorectal cancers) and diseases (cardiovascular events) potentially impacted by the chronic use of selenium and/or vitamin E. Other trial objectives will include periodic quality-of- life assessments, assessment of serum micronutrient levels and prostate cancer risk, and evaluation of biological and genetic markers associated with the risk of prostate cancer. The enrollment for SELECT began in 2001 and the final results are anticipated by 2013.16 The results may confirm the synergy between vitamin E and selenium that has already been established in animal studies5,14 and has been shown to lower prostate cancer incidence in humans. The study should also determine whether there is an independent effect of dl-α-tocopheryl acetate as a chemopreventive agent.

The same ester derivative of vitamin E (50 IU of dl-α- tocopheryl acetate) was administered by the wellknown Alpha- Tocopherol, Beta-Carotene (ATBC) cancer study, which resulted in a one-third reduction in prostate cancer incidence and a 41% reduction in prostate cancer mortality among Finnish male smokers.17 While the ATBC study showed a protective effect of vitamin E supplementation on prostate cancer entirely among smokers, the US Health Professional Study (USHPS) revealed a slightly reduced risk among smokers but none among non-smokers taking regular vitamin E supplements (50, 200, 400, or 800 IU).18 Thus, studies in human subjects have been inconsistent in establishing the chemopreventive action of vitamin E, either alone or in combination with other antioxidants, on prostate cancer incidence in the non-smoking, healthy male population. The choice of the form of vitamin E, its dose, and duration may be determining factors in relation to its chemopreventive action.

Figure 1. Schematic diagram of the relationship between vitamin E and prostate cancer. AR, androgen receptor; Fas-R, Fas receptor; PSA, prostate-specific antigen; VEGF, vascular endothelial growth factor; VES, vitamin E succinate.

The novel aspect of the study reported by Venkateswaran et al.5 is the combination of VES with selenium and lycopene as an effective antioxidant combination causing inhibition of prostate cancer when consumed daily in mice. Thus, VES, independently or in combination with other antioxidants, has been reported to be an effective chemopreventive agent.5,9-15 By itself, when administered through routes that bypass its hydrolysis to α-tocopherol, VES exerts a dramatic anti-neoplastic action through its accumulation in cancer cells.15,19 Considering the rising incidence of morbidity and mortality due to prostate cancer malignancy among US men, further research is warranted into the effects of the various forms and doses of vitamin E, alone and in combination with other antioxidants, as a potential chemopreventive agent.

REFERENCES

1. American Cancer Society. Cancer Facts & Figures 2004. Available online at: http://www.cancer.org/ downloads/STT/ CAFF_finalPWSecured.pdf. Accessed June 8, 2005.

2. Freeman VL, Meydani M, Yong S, et al. Prostatic levels of tocopherols, carotenoids, and retinol in relation to plasma levels and self-reported usual dietary intake. Am J Epidemiol. 2000;151:109- 118.

3. Willis MS, Wians FH. The role of nutrition in preventing prostate cancer: a review of the proposed mechanism of action of various dietary substances. Clin Chirm Acta. 2003;330:57-83.

4. Kamal-Eldin A, Appelqvist LA. The chemistry and antioxidant properties of tocopherols and tocotrienols. Lipids. 1996;31:671- 701.

5. Venkateswaran V, Fleshner NE, Sugar LM, Klotz LH. Antioxidants block prostate cancer in Lady transgenic mice. Cancer Res. 2004;64:5891-5896.

6. Fleshner N, Fair WR, Huryk R, Heston WDW. Vitamin E inhibits the high-fat diet promoted growth of established human prostate LNCaP tumors in nude mice. J Urol. 1999;161:1651-1654.

7. Neuzil J. Vitamin E succinate and cancer treatment: a vitamin E prototype for selective antitumour activity. Br J Cancer. 2003;89:1822-1826.

8. Venkateswaran V, Fleshner NE, Klotz LH. Modulation of cell proliferation and cell cycle regulators by vitamin E in human prostate carcinoma cell lines. J Urol. 2002;168(4 part 1):1578- 1582.

9. Ripoll EA, Rama BN, Webber MM. Vitamin E enhances the chemotherapeutic effects of adriamycin on human prostatic carcinoma cells in vitro. J Urol. 1986;136:529-531.

10. Israel K, Yu W, Sanders BG, Kline K. Vitamin E succinate induces apoptosis in human prostate cancer cells: role for Fas in vitamin E succinate-triggered apoptosis. Nutr Cancer. 2000;36:90- 100.

11. Yu A, Somasundar P, Balsubramaniam A, Rose AT, Vona-Davis L, McFadden DW. Vitamin E and the Y4 agonist BA-129 decrease prostate cancer growth and production of vascular endothelial growth factor. J Surg Res. 2002;105:65-68.

12. Zhang Y, Ni J, Messing EM, Chang E, Yang CR, Yeh S. Vitamin E succinate inhibits the function of androgen receptor and the expression of prostatespecific antigen in prostate cancer cells. Proc Natl Acad Sci USA. 2002;99:7408-7413.

13. Zhang M, Altuwaijri S, Yeh S. RRR-α-tocopheryl succinate inhibits human prostate cancer cell invasiveness. Oncogene. 2004;23:3080-3088.

14. Zu K, Ip C. Synergy between selenium and vitamin E in apoptosis induction is associated with activation of distinctive initiator caspases in human prostate cancer cells. Cancer Res. 2003;63:6988-6995.

15. Malafa MP, Neitzel LT. Vitamin E succinate promotes breast cancer tumor dormancy. J Surg Res. 2000;93:163-170.

16. Klein EA, Lippman SM, Thompson IM, et al. The selenium and vitamin E cancer prevention trial. World J Urol. 2003;21:21-27.

17. Heinonen OP, Albanes D, Virtamo J, et al. Prostate cancer and supplementation with α-tocopherol and β-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst. 1998;90:440-446.

18. Chan JM, Stampfer MJ, Ma J, Rimm EB, Willett WC, Giovannucci EL. Supplemental vitamin E intake and prostate cancer risk in a large cohort of men in the United States. Cancer Epidemiol Biomarkers Prev. 1999;8:893-899.

19. Weber T, Lu M, Andera L, et al. Vitamin E succinate is a potent novel antineoplastic agent with high selectivity and cooperativity with tumor necrosis factor-related apoptosis-inducing ligand (Apo2 ligand) in vivo. Clin Cancer Res. 2002;8: 863-869.

Arpita Basu, MS, and Victorine Imrhan, PhD

Ms. Basu and Dr. Imrhan are with the Department of Nutrition and Food Sciences, Texas Woman's University, Denton, Texas.

Address for correspondence: Arpita Basu, Department of Nutrition and Food Sciences, Texas Woman's University, P.O. Box 425888, Denton, TX 76204-5888; Phone: 940-395-2789; Fax: 940-898-2634; E- mail: arpita_twu@hotmail.com.

Copyright International Life Sciences Institute and Nutrition Foundation Jul 2005

Source: Nutrition Reviews

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