Gods, Nuclear Weapons and Potent Pathways – How Gamma Tocotrienol Works Molecular Magic: The Mevalonate Pathway
Introduction: The mevalonate pathway is a hotbed of new research. It is best known to us through statins—which interrupt and downregulate the pathway at an early step, and thus lower cholesterol. But now scientists are realizing that this profoundly important cellular pathway is responsible for far more than the synthesis of cholesterol. It helps synthesize many highly significant molecules that impact health and disease, and influences vasoconstriction, inflammation, coagulation and oxidation. Key molecules in this pathway may be therapeutic targets for many disorders. Statins, by shifting this pathway, improve cardiovascular disorders, fatty acid disorders in diabetics, Alzheimer’s disease, certain kidney diseases, macular degeneration, rheumatoid arthritis, osteoporosis and even infection. Gamma tocotrienol is not only a strong antioxidant, but also offers some of the benefits of statins by influencing the mevalonate pathway in a unique and beneficial way. In particular, gamma tocotrienol helps protect and repair tissue damaged from radiation. Here, we interview internationally respected expert Martin Hauer-Jensen on gamma tocotrienol, the mevalonate pathway, and the possibility of protecting tissues from radiation damage.Biography: Martin Hauer-Jensen, MD, PhD, FACS, is Professor of Pharmaceutical Sciences, Surgery, and Pathology at University of Arkansas for Medical Sciences (UAMS) and Staff Surgeon at the Central Arkansas Veterans Healthcare System in Little Rock, Arkansas. He is an internationally recognized authority on radiation effects in normal tissues, has been Chair of the Radiation Study Section of the NIH and a consultant on radiological emergencies to the World Health Organization (WHO). He is recipient of a Merit Award from the National Cancer Institute, and a recent $8.7 million contract from the Biomedical Advanced Research and Development Authority (BARDA) to work with UAMS on the development of a treatment for use in radiological or nuclear emergency situations.
Focus: A lot of your radiation research has explored gamma tocotrienol and how potent it is in preventing or repairing radiation damage-apparently by influencing the mevalonate pathway. I knew you were on to something big when I glanced at the astounding titles of some of the peer review papers by your colleagues, which you sent me, on the mevalonate pathway. The title of one refers to a particular molecule that is influenced by the pathway and calls it the “protectorate God of the vasculature.” You don’t often see titles suggesting that one single molecule is essentially God protecting the entire vasculature. Another paper title refers to the “nuclear weapon in the immune arsenal”- it’s like the scientists are shouting from the rooftop.1,2
Martin Hauer-Jensen (MHJ): Yes, perhaps we should express that in slightly more diplomatic terms than a nuclear weapon or God, but I strongly agree with these researchers. I think that what makes gamma tocotrienol such an effective radioprotector is precisely its impact on the mevalonate pathway. Although, of course, gamma tocotrienol is a potent antioxidant on its own.3
Surgeons sometimes have the dubious honor of trying to correct injury to the bowel due to radiation treatments for cancer. We hear about our patients’ sometimes crippling discomfort, and we see the tissue damage before our eyes. I wanted to find a way to help those patients.
Focus: How did you come to be so interested in gamma tocotrienol and radiation? You were originally a surgeon.
MHJ: I was originally a surgeon at the University of Oslo in Norway, although I’ve been at UAMS for 23 years. Surgeons sometimes have the dubious honor of trying to correct injury to the bowel due to radiation treatments for cancer. We hear about our patients’ sometimes crippling discomfort, and we see the tissue damage before our eyes. Quite simply, I wanted to find a way to help those patients.4 Around 2005, I was at a meeting in England when I was asked to contribute to a study conducted by Dr. Sree Kumar at the Armed Forces Radiobiology Research Institute (AFRRI) in Bethesda, MD. The study was to be on gamma tocotrienol and its ability to protect soldiers from radiation injury. At first I was skeptical. I wanted to study damage to the endothelial cells, and how that damage contributes to injury in the intestine. AFRRI, on the other hand, is interested in saving people from a nuclear attack. At the time, I also didn’t really think taking a vitamin pill would help first responders in a nuclear attack. But the more I researched gamma tocotrienol the more I realized that, where radiation was concerned, it was fundamentally different from other vitamin E analogs. It concentrates in endothelial cells at 50-100 fold more than any other vitamin E analog. The endothelium is the thin layer of cells that lines the interior surface of blood vessels and lymphatic vessels. It is profoundly impacted by the mevalonate pathway through HMG-CoA reductase, an important enzyme in that pathway. This pathway is increasingly being recognized for its importance in human health. The mevalonate pathway not only allows the body to produce cholesterol, it is also key to production of many other molecules, including ubiquinone (CoEnzyme Q10) and other molecules essential for cell growth and differentiation.
So all those facts about gamma tocotrienol really piqued my interest. We collaborated on the study, and I realized that gamma tocotrienol was a very, very potent radiation protector. These days, I have one foot in each camp—I work on radiation mitigators for nuclear emergencies, and also study patients who get radiation therapy for cancer. Traditionally, there has been some reluctance to develop medications that help against radiation side effects. It’s not as popular to say you’re fighting side effects as it is to say you’re fighting cancer. But lately that has begun to change, and there is an increasing focus from the National Cancer Institute on improving the efficacy and safety of cancer treatment, and maximizing the number of uncomplicated cancer cures.
Gamma tocotrienol is an incredibly interesting molecule with a good safety profile that might impact radiation induced tissue damage. It works quite a bit of molecular magic, in several unique ways.
Focus: How does gamma tocotrienol protect against radiation damage to tissue?
MHJ:First, it is an extraordinarily potent antioxidant that concentrates astonishingly well in the endothelial cells. There, it modulates the function of thrombin, and converts thrombin that has been generated inside blood vessels from a procoagulant into an anticoagulant. That means gamma tocotrienol puts a break on coagulation and platelet aggregation. Though thrombin is very important in repairing local injuries, it can be problematic when it is widespread, as in sepsis or radiation injury. Inflammation and coagulation are self-protective responses that are beneficial at sites of tissue injury. The molecule thrombomodulin ensures that thrombin formation is limited. Thrombomodulin allows important pro-coagulant molecules to act locally at the site of injury, and to stay there.
As to the protectorate God of the vasculature that you mentioned—thrombomodulin sits on the surface of just about every endothelial cell. Gamma tocotrienol concentrates astoundingly well in the same endothelial cells—fifty to a hundred times more than any other tocotrienol, and it upregulates thrombomodulin. It is ten times more effective than other members of the vitamin E family in reducing the expression of adhesion molecules. It is in a unique position among all the members of the vitamin E family.
Now, specific to radiation: in animal studies, radiation causes a sustained, dose-dependent decrease in microvascular thrombomodulin. That’s why an inexpensive, safe and effective strategy to help prevent or reverse tissue damage from radiation would be to upregulate thrombomodulin. That would have significant therapeutic potential. Gamma tocotrienol may be just that perfect strategy.5
Finally, gamma tocotrienol binds very strongly to a molecule called HMGB1 (High Mobility Group Box 1 protein), which was recently discovered to be a crucial molecule that mediates the response to infection, injury and inflammation. HMGB1 is the focus of new studies trying to understand its pathological effects in sepsis, arthritis, cancer and other diseases. And as to the nuclear weapon in the immune system’s arsenal—the other paper you mentioned—that paper discusses HMGB1 (High Mobility Group Box 1 protein). Thrombomodulin strongly binds HMGB-1, and thus gamma tocotrienol indirectly “downregulates” HMGB-1. HMGB-1 is a potent molecule that can function as a systemic mediator of many diseases. Similar to a conventional cytokine, HMGB1 activates endothelial cells, promotes angiogenesis, and initiates inflammation. HMGB1 overexpression is observed in many cancer cells. Interestingly, macrophages secrete HMGB1 much later than well-known cytokines like the interleukins or tumor necrosis factor. Those may be released in a few hours, whereas HMGB1 levels may increase about 12-18 hours after the other cytokines. Much research is being done now on the possibility of controlling HMGB1 activity as a treatment for sepsis, arthritis, cancer and other diseases.
Gamma tocotrienol, by upregulating thrombomodulin which binds HMGB1, is therefore an incredibly interesting molecule with a good safety profile that might impact the above diseases. It works quite a bit of molecular magic, in several unique ways.6
Focus: Can you tell us the results so far in animal studies of gamma tocotrienol and radiation damage?
MHJ: Originally, most of the radioprotective studies with vitamin E were done with alpha tocopherol. But in one study, when we compared the efficacy of alpha tocopherol and gamma tocotrienol on irradiated mice, we found that 40% of mice receiving gamma tocotrienol survived a lethal dose of radiation, while all given alpha tocopherol died.7
We know that gamma tocotrienol upregulates thrombomodulin, as I’ve said. And we know that thrombin itself activates receptors called PARs (proteinase-activated receptors). Studies in our laboratory show that intestinal radiation injury is associated with a striking upregulation of PAR1 in endothelium and smooth muscle cells. Some of the changes induced by radiation may become chronic and play direct roles in chronic injury.8
We also looked at whether gamma tocotrienol might work against radiation injury by inhibiting HMG-CoA reductase, a key enzyme in the mevalonate pathway. Groups of mice were treated with mevalonate, gamma tocotrienol alone, or the two combined. After exposure to total-body irradiation, gamma tocotrienol improved survival and decreased vascular damage. However, adding mevalonate could reverse this protective effect. Thus the radioprotective efficacy of gamma tocotrienol against vascular injury is related to its properties as an HMG-CoA reductase inhibitor.9,10
In another study, we found that gamma tocotrienol protected hematopoietic stem cells in mice after total body irradiation. The mice were given sub-lethal doses of total body irradiation, which depleted their hematopoietic stem cells. Mice treated with gamma tocotrienol recovered their hematopoietic stem cells almost completely (90%) by seven days, while most mice given a placebo were still depleted after 13 days. When we examined the bone marrow, we found more regeneration in the mice treated with gamma tocotrienol. The implications for this are profound, since we know that bone marrow suppression is a limiting factor for chemotherapy and radiotherapy in cancer, and self-renewal of stem cells is necessary to restore health.11
We also saw interesting results in a study on gamma tocotrienol and G-CSF (granulocyte colony stimulating factor), an immune boosting molecule. Though this finding is not ready for prime time yet, we did find that gamma tocotrienol induced high levels of G-CSF in mice.12
Focus: What lies ahead?
MHJ: We plan to test gamma tocotrienol in a clinical trial in humans. We will study patients with chronic radiation-induced rectal injury, and see if we can improve the tissue injury, or at least stop it from developing further. We will combine gamma tocotrienol and a drug called pentoxifylline, which improves blood flow to tissue.13 These patients have had radiation in the past for cancer, and have then developed a crippling disorder of the rectum or anus. The investigator I work with is Jervoise Andreyev, who is the only gastroenterologist in the world whose entire practice is focused on helping these patients with radiation-induced gastrointestinal injury. We anticipate enrollment to start soon and have high hopes for the study.14
- Ito T, Maruyama I. Thrombomodulin: protectorate God of the vasculature in thrombosis and inflammation. Journal of Thrombosis and Haemostasis, 9 *Suppl. 1): 168-173.
- Lotze MT, Tracey KJ. High-Mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nature Reviews, Vol. 5, 205. p. 331-342.
- Ghosh SP, Kulkarni S, Hieber K, Toles R, Romanyukha L, Kao TC, Hauer-Jensen M, Kumar KS. Gamma-tocotrienol, a tocol antioxidant as a potent radioprotector. Int J Radiat Biol. 2009 Jul;85(7):598-606. PMID 19557601 View Abstract
- Denham JW, Hauer-Jensen M. Radiation induced bowel injury: a neglected problem. Lancet. 2013 Dec 21; 382(9910):2046-7. PMID 24067489 View Abstract
- Geiger H, Pawar SA, Kerschen EJ, Nattamai KJ, Hernandez I, Liang HP, Fern•ndez J¡, Cancelas JA, Ryan MA, Kustikova O, Schambach A, Fu Q, Wang J, Fink LM, Petersen KU, Zhou D, Griffin JH, Baum C, Weiler H, Hauer-Jensen M. Pharmacological targeting of the thrombomodulin-activated protein C pathway mitigates radiation toxicity. Nat Med. 2012 Jul;18(7). PMID: 22729286 View Abstract
- Berbèe M, Fu Q, Boerma M, Sree Kumar K, Loose DS, Hauer-Jensen M. Mechanisms underlying the radioprotective properties of y-tocotrienol: comparative gene expression profiling in tocol-treated endothelial cells. Genes Nutr 2012 Jan:7(1). PMID: 21516479 View Abstract
- Kumar KS, Ghosh SP, Hauer-Jensen M: Chapter 27. Gamma-tocotrienol: potential as a countermeasure against radiological threat. In: Tocotrienols – Vitamin E beyond Tocopherols. Ed. Watson RR, Preedy VR. CRC Press, Boca Raton, FL, 2009, pp. 379-398.
- Wray J, Williamson EA, Singh SB, Wu Y, Cogle CR, Weinstock DM, Zhang Y, Lee SH, Zhou D, Shao L, Hauer-Jensen M, Pathak R, Klimek V, Nickoloff JA, Hromas R. PARP2 is required for chromosomal translocations. Blood. 2013 May 23; 121(21). PMID: 23568489 View Abstract
- Kulkarni S, Ghosh SP, Satyamitra M, Mog S, Hieber K, Romanyukha L, Gambles K, Toles R, Kao TC, Hauer-Jensen M, Kumar KS. Gamma-tocotrienol protects hematapoietic stem and progenitor cells in mice after total-body irradiation. Radiat Res. 2010 Jun;173(6):738-47. PMID: 20518653 View Abstract
- Berbèe M, Fu Q, Boerma M, Wang J, Kumar KS, Hauer-Jensen M. Gamma-tocotrienol ameliorates intestinal radiation injury and reduces vascular oxidative stress after total-body irradiation by an HMG-CoA reductase-dependent mechanism. Radiat Res. 2009 May;171(5):595-605. PMID 195804985 View Abstract
- Ray S, Kulkarni SS, Chakraborty K, Pessu R, Hauer-Jensen M, Kumar KS, Ghosh SP. Mobilization of progenitor cells into peripheral blood by gamma-tocotrienol: a promising radiation countermeasure. Int Immunopharmacol. 2013 Mar; 15(2): 557-64. PMID: 23415908 View Abstract
- Kulkarni SS, Cary LH, Gambles K, Hauer-Jensen M, Kumar KS, Ghosh SP. Gamma-tocotrienol, a radiation prophylaxis agent, induces high levels of granulocyte colony-stimulating factor. Int Immunopharmacol. 2012 Dec; 14(4):4954-503. PMID: 23000517 View Abstract
- Sridharan V, Tripathi P, Sharma S, Corry PM, Moros EG, Singh A, Compadre CM, Hauer-Jensen M, Boerma M. Effects of late administratin of pentoxifylline and tocotrienols in an image-guided rat model of localized heart irradiation. PLoS One. 2013 Jul 22;8(7):PMID: 23894340 View Abstract
- Berbèe M, Hauer-Jensen M. Novel drugs to ameliorate gastrointestinal normal tissue radiation toxicity in clinical practice: what is emerging from the laboratory? Curr Opin Support Palliat Care. 2012 Mar; 61):54-9. PMID 22228028 View Abstract
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