In the United States, prostate cancer is the second leading cause of new cancer cases, accounting for approximately 33% of all new cases in males and is the second leading cause of cancer-related death of men, behind lung cancer. Factors such as diet, exercise, and environment are all aspects related in the subsequent development of cancers. For example, statistics from the American Cancer Society show that the death rates of prostate cancer are greater in the United States compared to China.

Epidemiological studies have indicated the protective roles of certain vitamins and minerals in prostate cancer. Among these vitamins and minerals, vitamin E has been identified by researchers as a potent anticancer agent in the delay or prevention of prostate cancer. There is a variety of factors that affect the performance and effectiveness of vitamin E in the body. The method by which vitamin E is taken into the body is an area of concern. Another consideration is the efficacy of different isoforms of vitamin E including four tocopherols and four tocotrienols. There are also numerous synthetic vitamin E analogs that have been proven to be effective in vivo, such as α-vitamin E succinate (VES).

In vivo animal and clinical studies support in vitro data on the effectiveness of vitamin E in curbing the growth of cancers through a variety of mechanisms including cell cycle inhibition, apoptosis, gene regulation, and antioxidation. This review discusses anticancer mechanisms of vitamin E other than its antioxidant activity, and supporting animal and clinical data. Upcoming clinical trials and a look at future study directions are also included.

Vitamin E and Its Analogs

Vitamin E refers to a family of compounds called tocopherols and tocotrienols. Both groups are further divided into four isoforms: α, β, γ, and δ. α-Tocopherol is the most commonly found natural form of vitamin E as it accounts for about 90% of all tocopherols in most mammalian tissues. It has several esterified analogs including α-tocopheryl acetate (α-vitamin E acetate, VEA), α-tocopheryl nicotinate (α-vitamin E nicotinate, VEN), and α-tocopheryl succinate (α-vitamin E succinate, VES). Of all these forms, VES (vitamin E succinate) is the most effective in terms of its anticancer properties. Both in vitro and in vivo studies have shown that VES is capable of inducing apoptosis and inhibiting cell proliferation in cancer cells without affecting the proliferation of most normal cells. VES can be hydrolyzed by esterase in the gastrointestinal tract and may thus lose some of its potency. In vivo animal studies have shown that an intraperitoneal injection is an effective delivery strategy of the VES. A non-hydrolyzable ether forms, α-tocopheryl oxybutyric acid and ether acetic acid analogs, have been created as a solution for this loss of potency.

In addition, Birringer et al. have shown that the modification of different functional moieties of the vitamin E molecule can enhance its proapoptotic properties. Analogs of VES with a lower number of methyl substitutions on the aromatic ring were less active than VES itself. Replacement of the succinyl group with a maleyl group greatly enhanced the activity. However, methylation of the free succinyl carboxyl group on VES completely abolished the apoptogenic activity of these compounds.

Vitamin E Absorption and Transport

Major dietary sources of vitamin E include vegetable oils, margarine, nuts, seeds, whole grains, soybeans, eggs, and avocados. The recommended dietary allowance of vitamin E is 15 mg/day (15 mg = 22.5 IU), however, common doses range from 100 to 800IU/day with no significant adverse side effects, and have not been associated with mutagenic or teratogenic properties.

Vitamin E is absorbed in the intestine and circulates through the lymphatic system. It is absorbed together with lipids, packed into chylomicrons, and transported to the liver. This process is similar for the various forms of vitamin E. After transport to the liver, α-tocopherol will be absorbed and released to the plasma. Most other ingested β-, γ-, and δ-tocopherols and tocotrienols are secreted into bile, or not absorbed and excreted in the feces.

In the American diet the level of consumption of γ-tocopherol ranges from two to four times higher than the level of α-tocopherol. Both forms are equally well absorbed by the intestines, bound with chylomicron lipoprotein, and transported to liver, yet the plasma level of α-tocopherol is five to ten times higher than plasma levels of γ-tocopherol. This is attributed to α-tocopherol’s higher affinity to a liver cytosolic tocopherol transfer protein (TTP) compared to γ-tocopherol. Therefore, TTP is a major determinant of plasma tocopherol levels. There have been studies that show that dietary supplementation with α-tocopherol will actually decrease levels of γ-tocopherol in the blood and adipose tissue due to the limited binding capacity of the hepatic TTP.

Furthermore, Bonina’s study indicates that α-tocopherol and VES (α-tocopheryl succinate) are incorporated into erythrocyte membranes with the help of specific transport proteins. The study suggested that other vitamin E transfer or binding proteins could exist and differences in membrane incorporation of α-tocopherol and VES might contribute to their variant cytoprotective properties. Indeed, other vitamin E binding proteins, the tocopherol associated protein and tocopherol binding protein, were identified, but their functions were not fully characterized.

Functional Mechanisms of Vitamin E in Prostate Cancer

Currently, a new clinical trial, SELECT, has been initiated in the US, and an earlier epidemiological study also indicated that daily supplements of Vitamin E could reduce the incidence and mortality of prostate cancer. However, the functional mechanisms remain largely unclear. We summarize the functional mechanisms of vitamin E as follows.

Vitamin E and Its Analogs Induce Proapoptotic Properties in Prostate Cancer Cells

α-Vitamin E (α-tocopherol) has been shown by researchers to have proapoptotic properties in human prostate cancer LNCaP cells. Their data showed that vitamin E administration resulted in reduced DNA synthesis and enhanced DNA fragmentation, as well as a general inhibition of cell proliferation.

Another study by Gunawardena and colleagues, showed that α-tocopherol stimulated apoptosis in three different human prostate cancer cell lines: DU-145 (androgen-unresponsive), LNCaP (androgen-responsive), and ALVA-101 (moderately androgen-responsive). The group cited nucleosome fragmentation as evidence of apoptosis following α-tocopherol treatment in these different prostate cancer cell lines.

Furthermore, results from other researchers indicated that the apoptosis-triggering properties of VES may be due to its modulation of Fas signaling. Fas belongs to the tumor necrosis factor receptor and nerve growth factor receptor superfamily, and contains a cytoplasmic death domain that can initiate an apoptotic cascade. Using two prostate cancer cell lines (LNCaP and PC-3) and the normal prostate epithelial cells (PrEC) the investigators showed that VES induced apoptosis only in cancer cells. They also showed that VES administration enhanced Fas ligand expression and increased Fas levels in the membrane, both of which are important events in Fas-induced apoptosis.

Vitamin E and Its Analogs Inhibit Cell Cycle Progression

VES has been shown to inhibit the proliferation of prostate cancer cell lines through the inhibition of cell cycle. Our group has found that VES effectively inhibits prostate cancer LNCaP cell growth by causing cell cycle arrest in the G1 phase with a reduction of cells in S phase. VES decreases the expression of several cell cycle regulatory proteins such as cyclin D1, D3, E, cdk2, and cdk4, but not cdk6. In addition, Ni et al. also found that VES can inhibit the phosphorylation of retinoblastoma (Rb), and consequently inhibit the E2F activity. Another group, Venkasteswaran et al, has observed similar inhibitory effects of VES. Their data shows VES-induced G1 arrest in LNCaP and G2/M arrest in PC-3 prostate cancer cells. Their data also showed a G1 phase arrest, and the mechanism credited for the increased amounts of p27 by VES.

In addition to α-tocopherol, γ-tocopherol is another isoform of vitamin E that has demonstrated anticancer properties. A study by Gysin and colleagues showed that γ-tocopherol inhibits cell proliferation more significantly than α-tocopherol in DU-145 and LNCaP cells. They also showed that the mechanisms of γ-tocopherol are through inhibition of DNA synthesis, defects of cell cycle with decreased S-phase cell population, and down-regulation of cyclin Dl and cyclin E levels. Based on their results, γ-tocopherol is more potent than α-tocopherol in those two cell lines. However, the absorption efficiency of γ-tocopherol is lower than that of α-tocopherol in human.

VES Inhibits the Expressions of PSA and the Androgen Receptor (AR)

A functional AR is essential for the development and progression of prostate cancer. In prostate, AR can bind to the promoter of and regulate the expression of prostate-specific antigen (PSA), the most popular detection marker for prostate cancer. Results from our earlier report suggested that VES, at a non-toxic concentration and in vivo achievable level, could selectively inhibit the expression of both AR and PSA, but not retinoid X receptor a (RXRa) and peroxisome proliferators-activated receptor a (PPARa), in prostate cancer LNCaP cells. Results from further investigation indicated that VES can affect the translational efficiency of AR. Overall, the results suggested that VES-mediated inhibition of prostate cancer cell growth can be partly due to the inhibition of AR function.

VES Inhibits Activity of MMP9 Secreted From Prostate Cancer Cells

Most of the tumors of prostate cancer patients become incurable once their cancers progress to metastatic stage. Metastasis of cancer cells employs complicated processes including degradation of extracellular matrix, migration, homing and angiogenesis. Our group has found that VES can affect the invasiveness of prostate cancer PC-3 and DU-145 cells. Results from mechanism investigation suggested that VES could affect the matrix metalloproteinase-9 (MMP-9) activity, but not the tissue inhibitor of metalloproteinases (TIMPs). The inhibition of MMP-9 activity and cancer metastasis through matrigel could be observed with 24 h treatment of VES. This time frame is shorter then the event of VES mediated disturbance of the cell cycle distribution and cell growth, which takes action upon longer VES treatment. Thus, the inhibition of MMP-9 activity could be an event independent of VES-mediated cell growth inhibition and cell cycle progression of prostate cancer cells.

Summary

Although some controversial data exists, the epidemiological and clinical studies suggested that the incidence and mortality of prostate cancer may be reduced with daily supplement of α-tocopherol analogs. We and other researchers have devoted efforts on exploring these underlying mechanisms. Currently, the identified mechanisms include inhibition of DNA synthesis, inducing apoptosis and FAS ligand activity, affecting the expression and function of AR and PSA, targeting on cell cycle molecules, and inhibiting the invasiveness of prostate cancer cells. There are still several fields have not been addressed. First, it is of great interest to know whether α-tocopherol and its analogs can affect the growth factor and kinase signals, oncogene function, bone metastasis, and angiogenesis in prostate cancer cells. Second, as most of the published results rely on the in vitro cell line studies, it is important to use animal models to test the anticancer effects of α-tocopherol and its analogs. The application of animal models, including cancer cell xenografts on nude mice, transgenic mice such as TRAMP model, LADY prostate cancer model, knockout mice models such as NKX3.1 knockout mice, pTENknockout mice and others, could advance our insights of how α-tocopherol affects the development of prostate cancer in vivo. Third, there is a need to identify the α-tocopheryl derivatives with better efficacy and stability than the parental chemical version. Fourth, the exploration of the roles of tocopherol-associated protein (TAP) and tocopherol transfer protein (TTP) are also important. Till now, TTP is the only protein that has been linked to the absorption of tocopherol into liver and then subsequently into circulating systems. However, the roles of another tocopherol binding protein, TAP, have not been well-explored. Fifth, among these fat-soluble vitamins, A, D, E, and K, the receptors of vitamin A and vitamin D have been identified. It is interesting to investigate whether vitamin E has a specific receptor, which can bind and propagate the function and signal of vitamin E. Overall, the anticancer effects of vitamin E and its analogs have been observed, yet the underlying mechanisms need more intensive investigations. Although there have been many advances in radiotherapy, chemotherapy, and surgery, the use of complementary therapies for cancer remains of key interest. Understanding the functional mechanisms of vitamin E are important, as they will provide a base for the combinational therapy with other compounds. In the long run, cancer patients could benefit from a cocktail therapy via combining different treatments with complementary or synergistic effects.

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