Tocotrienols: latest cancer research in vitamin E.
Subject: Tocotrienols (Health aspects)
Vitamin E (Health aspects)
Cancer (Care and treatment)
Cancer (Patient outcomes)
Cancer (Methods)
Authors: Tan, Barrie
Trias, Anne M.
Pub Date: 08/01/2012
Publication: Name: Townsend Letter Publisher: The Townsend Letter Group Audience: General; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2012 The Townsend Letter Group ISSN: 1940-5464
Issue: Date: August-Sept, 2012 Source Issue: 349-350
Product: Product Code: 8000432 Cancer Therapy NAICS Code: 621 Ambulatory Health Care Services SIC Code: 2833 Medicinals and botanicals
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 303012897
Full Text: As of late, there has been no good news about vitamin E. The supplement has drawn bad reviews for its lack of benefits for cardiovascular health, while a large-scale clinical study even found that it increased the risk of prostate cancer. Despite this discrediting media coverage, we would be gravely mistaken to neglect vitamin E altogether. As opposed to common belief, vitamin E is not a single compound, but a family of at least eight similar, yet structurally different, molecules. While the once popular vitamin E alpha-tocopherol falls from stardom, tocotrienol--the lesser-known form of vitamin E--shores up benefits for cardiovascular health, and is currently under investigation for cancer therapy and prevention.

Structured for Success

Tocotrienols are derived from three major sources: palm, rice, and annatto. While palm and rice yield a tocotrienol-tocopherol mixture, annatto is the only tocopherol-free source of tocotrienols. This is an important feature, since research of the past 20 years has shown alpha-tocopherol as a culprit in interfering with tocotrienol benefits, both cardiovascular and cancer. (1-3)

Tocotrienols differ from tocopherols as a result of their more flexible chemical structure, allowing them to efficiently cover larger membrane areas for added protection. In addition to its superior antioxidant, hypocholesterolemic, and antithrombotic activities, tocotrienol has shown consistent antitumor benefits. Delta- and gamma-tocotrienol's superior anticancer function to that of alpha is also due to structural differences. Alpha-tocotrienol has a much bulkier head, which is due to three extra methyl groups that are attached to the molecule. Gamma-tocotrienol has two extra methyl groups, while delta-tocotrienol has only one extra methyl group. Delta-and gamma-forms of vitamin [are also simply called "desmethyl" vitamin E due to reduced methyl groups in the molecule's head region.

How They Work on Cancer

There are many possible modes of action for cancer prevention/therapy by tocotrienols. Some researchers attribute tocotrienols' anticancer effects to their potent antioxidant activity, since they efficiently protect cells from free-radical damage. (4) Others believe that the anticancer activity may be due to tocotrienols' ability to downregulate and degrade the enzyme responsible for cholesterol synthesis in the body (HMG-CoA reductase), which is aberrant in cancer.(5), (6) Tocotrienols also appear to activate caspase-3 pathways, hence inducing programmed cell death (apoptosis) of cancer cells. (7) Finally, tocotrienols have been shown to inhibit angiogenesis, which in cancer is the abnormal growth of blood vessels. (8), (9) The tumor uses these new and unusual blood vessels to obtain nutrients to fuel its growth. Recent studies showed that tocotrienols--but not tocopherols--inhibit angiogenesis, cutting the nutrient lifeline to the tumor and essentially starving it to death. This occurs because tocotrienols reduce vascular endothelial growth factor (VEGF), a protein involved in regulating these aberrant blood vessels. Tocotrienols downregulate the receptor for VEGF, therefore blocking intracellular signaling of this protein and inhibiting angiogenesis. (9) In addition, tocotrienols inhibit the tube formation of bovine aortic endothelial cells (an in vitro model that mimics blood vessel formation), where delta-tocotrienol had the strongest inhibitory activity. (10) Since angiogenesis is essential to tumor growth, its inhibition likely stunts tumor growth and prevents cancer metastasis.

Tocotrienols may well work on dual antitumor mechanisms that include the removal of the vital nutrient-to-tumor lifeline (via inhibiting angiogenesis) and the targeting of tumor cells via signals to successfully obstruct cancer pathways. (7), (11)

What Cancers They Work On

To date, tocotrienols seem to perform well in all cancer cell lines that they have been studied on. In animal studies, cancer inhibition by tocotrienol has been shown for breast, prostate, pancreas, skin, lung, liver, and colon, with delta- and gamma-tocotrienol being most effective.

Breast Cancer: Breast cancer is the leading cancer among white and African American women, with an approximate 275,000 new cases and estimated 41,000 deaths each year in the US. Tocotrienols have been shown to halt the proliferation of human breast cancer cells, whereas alpha-tocopherol is ineffective. (12) As opposed to the drug tamoxifen used in estrogen--receptor positive breast cancer patients, tocotrienol works irrespective of estrogen receptor status, with gamma- and delta-tocotrienol being the most potent. (13), (14) A previous breast cancer clinical trial used tocopherol-tocotrienol mixture, but this therapeutic agent will be replaced with pure gamma-tocotrienol, presumably to avoid tocopherol interference issues. (15) Alpha-tocopherol not only interferes with tocotrienol functions, but also antagonizes DHA's anticancer properties. (16) Gamma-tocotrienol, on the other hand, enhanced DHA's effect. Unfortunately, dietary vitamin E only contains a very small amount of desmethyl tocotrienols (<10%), and a large amount of tocopherols (>90%, particularly alpha-tocopherol), which have no effect in the treatment of cancer, making supplementation a necessity for adequate tocotrienol accumulation in the body. For breast cancer, the safety of tocotrienols has been well documented, where no or only low levels of apoptosis occurred in healthy breast epithelial cells. (17-19)

Pancreatic Cancer: Pancreatic cancer remains the most lethal of all cancers, with only a 6% survival rate (about 1 in 20). Steve jobs, Patrick Swayze, Luciano Pavarotti, Dizzy Gillespie, and Count Basie all have died of this disease. Supreme Court justice Ruth Bader Ginsburg is living with it. A compelling phase I dose-escalation trial on delta-tocotrienol in patients with surgically removable pancreatic cancer is under way and so far shows no adverse effects up to 3200 mg/day, while cancer cell death in patients was observed at the lowest dosage of 200 mg/day. (20), (21) Further analysis of tissue specimens and a phase II trial are planned. Other cell line and animal studies undertaken by independent research groups clearly underscore and lend unambiguous support to delta-tocotrienol's effect on pancreatic cancer. (20), (21), (22) Here, delta-tocotrienol inhibited pancreatic tumor growth, blocked malignant transformation, induced cancer cell death, and accumulated in the pancreas 10x more than in the liver and tumor. Researchers clearly prefer the use of delta-tocotrienol and/or gamma-tocotrienol for these studies, while the composition should be free of alpha-tocotrienol, beta-tocotrienol, and other tocopherols. (24)

Prostate Cancer: Prostate cancer is the cause of ~ 30,000 deaths per year in the US and is, after lung cancer, the leading cause of cancer deaths in men. (25) Many are aware of the disappointing results of the recent Selenium and Vitamin E Cancer Prevention Trial (SELECT), which shockingly revealed a 17% increase in prostate cancer risk with vitamin E supplementation. This clinical trial, however, used synthetic a-tocopheryl acetate. Tocotrienols, on the other hand, particularly delta-and gamma-tocotrienol, were shown to have inhibitory effects on several types of prostate cancer cell lines. Delta-tocotrienol most effectively induced cell death of prostate cancer cells, and activated programmed cell death while disrupting NFkB signaling. (26), (27)

Lung and Liver Cancer: Without doubt, the single leading cause of cancer deaths in both sexes is lung cancer, primarily caused by lifestyle habits. Non-small cell lung cancer accounts for 80% of lung cancers. Delta-tocotrienol treatment of nonsmall lung cancer cells resulted in a dose-and time-dependent inhibition of cell growth, and was associated with downregulation of genes via NFkB inhibition. (28) Delta-tocotrienol inhibited lung cancer cell proliferation, induced cancer cell death, and prevented cell cancer invasion. (28), (29) Additionally, an alpha-tocotrienol analogue decreased human lung adenocarcinoma by suppressing hypoxia--a lack of oxygen--in the tumor. (30), (31)

Gamma-tocotrienol has also been shown to block the activation of a critical pathway (STAT3) in the survival, proliferation, angiogenesis, and chemoresistance of cancerous liver cells. (32) A recent in vivo and in vitro study showed suppression of liver and lung carcinogenesis in mice. Delta-tocotrienol potently induced apoptosis and S-phase arrest while increasing CYPIAI gene, a phase I enzyme. (33)

Colorectal Cancer: Excluding skin cancers, colorectal cancer is the third most common cancer diagnosed in both sexes, and the second leading cancer killer in the US. The American Cancer Society's most recent estimates for the number of colorectal cancer cases in the US are 101,340 new cases of colon cancer and 39,870 new cases of rectal cancer in 2011. (34) Delta-tocotrienol was shown to induce paraptosis-like cell death in colon cancer celk, and was associated with suppression of the Wnt signaling pathway, a network of proteins crucial in embryogenesis, but also involved in cancer. (35) Likewise, gamma-tocotrienol induced colon and gastric cancer cell death accompanied by activation of caspase-3. (36), (37) Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis have been linked to an almost 20-fold increase in the risk of colon cancer, and tocotrienols may inhibit the excessive fibroblast expansion associated with these diseases. (38), (39)

Melanoma and Tocotrienol's Protective Effect on Skin: Melanoma is the deadliest type of skin cancer, causing about 8000 deaths in the US each year. (40) Gamma- and delta-tocotrienol inhibited melanoma cells and produced tumor retardation in animals with highly metastatic melanoma. Tocotrienol-treated animals also experienced prolonged survival rates. (41) Gamma- and delta-tocotrienol in combination with lovastatin are even more potent in melanoma inhibition in cell line and animal studies. (42)

Vitamin E is known to be a superior protector against environmental stressors such as UV-irradiation of the skin. (43) A tocopherol-tocotrienol mixture has significantly higher potency than alpha-tocopherol alone, and is effective against protein oxidation and lipid peroxidation at low concentrations.44*45 Normally, UV-irradiation destroys the antioxidants of the skin, but prior application of tocopherol-tocotrienol mixture to mouse skin preserved the vitamin E. (46) Also, the largest fraction of vitamin E was found in the subcutaneous layer of the skin, which shows that applied vitamin E penetrates rapidly through the skin, and therefore combats oxidative stress induced by UV or ozone efficiently. (47), (48) Delta-and gamma-tocotrienol in particular have been shown to reduce inflammation. (49-51) In addition, they are potent skin whitening agents via reduction of tyrosinase activity (an enzyme that speeds up oxidation of an important amino acid), while also blocking UV-induced melanoma formation. Delta-tocotrienol has the greatest sun protection factor (SPF) of the tocotrienol isomers at SPF 5.5. (52) In other words, warding off skin cancer later in life is the maintenance of skin health earlier in life.

Other Emerging Benefits

Over the last few years, tocotrienol research interest has expanded into other categories related to cancer, including tocotrienol's anti-inflammatory benefits and its potential as radiation countermeasure agent.

Inflammation: Tocotrienols have potent anti-inflammatory properties and were shown to decrease NFkB, a family of proteins that regulate inflammation and immunity, but are also instrumental in chronic inflammation, cancer, and aging. New research focused on the effect of tocotrienols in reducing inflammation in animals, and demonstrated that alpha-, gamma-, and delta-tocotrienols strongly inhibited the inflammatory response, with delta-tocotrienol being the most effective. The study examined factors that are often associated with inflammation such as chymotrypsin, trypsin, and tumor necrosis factor-a (TNF-a). (49) According to study results, tocotrienols increase the immune system's ability to fight inflammation, and also enhance the body's ability to discard unneeded or damaged proteins by modulating large protein complexes called proteasomes. At the same time, tocotrienols induce a hormone that produces an anti-inflammatory steroid to block inflammation directly.

Radiation Countermeasures: Delta-and gamma-tocotrienols may have important implications in radiation oncology, as promising research uncovered their radioactive countermeasure capabilities. In the past six years, the Armed Forces Radiobiology Research Institute (AFRRI, Bethesda, MD) has extensively researched tocotrienol as a radiation countermeasure agent. (54) Of the tocotrienols, delta-and gamma-tocotrienol are among the most effective radioactive countermeasure agents. (55, (56) Tocotrienols are known to combat reactive oxygen species (ROS) and reactive nitrogen species (RNS), the primary source of radiation-induced damage; and the fact that tocotrienols have potent antioxidant properties lends support to AFFRI's original hypothesis--"strong antioxidants make strong radioprotectors." (57) Beyond antioxidation, tocotrienols are also involved in amelioration of radiation lethality, which is usually acute and severe. Moreover, delta-and gamma-tocotrienol display an unambiguous stimulatory effect on the bone marrow, the first line of insult by radiation to the human body, restoring the fresh blood supply. (55), (58) Tocotrienols almost fully restored bone marrow cellularity to normal levels following radiation, while overall cellularity in untreated controls remained depleted: (55), (56) In both cases, prophylactic treatment 24 hours preradiation was more effective than postradiation treatment. This part is especially important for cancer patients undergoing radiation therapy.

Aside from application in radiation oncology, delta-and gamma-tocotrienol could be used as powerful radioprotectors for first responders to nuclear fallout areas and radiation workers.

Summary

Tocotrienols--but not tocopherols and, in particular, not alpha-tocopherol--have repeatedly been shown to inhibit proliferation and induce cancer cell death, and cells with the greatest degree of malignancy are most sensitive to the apoptotic action of tocotrienol. (7), (30), (33) Delta-tocotrienol and gamma-tocotrienol are most potent for cancer applications, particularly for breast, prostate, colorectal, and lung cancer, while delta-tocotrienol is a rising star in groundbreaking clinical trials for pancreatic cancer.

Currently, tocotrienols have reached a new measure of research height: more than one-third of all vitamin E tocotrienol research of the last 30 years was published in the last three years (2009-2011). Of these publications, the limelight is on cancer research. The media's discredit of vitamin E--applying only to alpha-tocopherol--should not be confused with tocotrienol.

Notes

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by Barrie Tan, PhD, and Anne M. Trias, MS

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Barrie Tan, PhD, earned his bachelor's degree in chemistry and a doctorate in analytical chemistry at the University of Otago, New Zealand. He later became a professor of chemistry and food science/nutrition at the University of Massachusetts, Amherst. His research expertise includes lipid-soluble materials such as carotenoids, tocotrienols/tocopherols, CoQ10, omega-3s, and cholesterol. He was the first to introduce tocotrienol's benefits to the nutrition industry. He founded American River Nutrition Inc. in 1998 and developed the first-ever tocopherol-free tocotrienol product derived from annatto beans. Today, the focus of his research is on phytonutrients that have an impact on chronic, degenerative, and cancer diseases. Dr. Tan was elected to be senior editor of the second-edition tocotrienol compilation Tocotrienols: Vitamin E Beyond Tocopherols (2012).

Anne Trias, MS, received her master of science in microbiology from the University of Massachusetts, Amherst. Her thesis centered on tocotrienol's attenuating effect on chlamydial infections. Ms. Trias joined American River Nutrition Inc. in 2006, where she is actively involved in technical writing and sales, and R&D management. Currently, she is a member of the organizing committee for the 2nd International Tocotrienol Symposium held in conjunction with the 103rd Annual Meeting of the American Oil Chemists' Society.
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