Dietary Program
Dietary Restriction and Cancer
Dietary restriction is important because it limits the nutrients that supply the rapid cancer growth. Based on this concept, at Ixtapa, we limit total calorie intake, carbohydrate intake, and the intake of the amino acids phenylalanine, tyrosine, and methionine. Cancer patients should eat no more than 1,500 calories per day (the less they consume, the better – short of exhibiting immune suppression from malnutrition). Carbohydrate intake should be no more than 40% of the total calorie intake. The amino acids mentioned above should be restricted, especially until the patient has shown to either stabilize the cancer or go into remission. This restriction can be accomplished by avoiding meat products, beans, nuts, seeds, and whole grains. The protein intake will be replaced by whey protein, at 30 grams per day and a proprietary amino acid formula which is depleted in the above-mentioned amino acids. At our Ixtapa facility, we ensure that our cancer patients are provided with foods and meal replacements that are consistent with the above-mentioned concept.
Supplements that Inhibit Cancer Growth
Myco-Immune Complex - Each capsule of MMIE contains organic full spectrum mycelia and standardized extracts of:
Agaricus blazei 58.5% Beta-Glucans (1-6, D-Beta Glucan)
Cordyceps sinensis 30% Beta-Glucans, deoxyadenosine and other nucleosides)
Maitake (Grifola frondosa) 28% Beta-Glucans (Protein bound Fraction extracted according to Dr. Nanba’s original formula)
Shiitake (Lentinus edodes) 40 % Beta-Glucans (including lentinan, alpha-glucan KS-2)
Coriolus versicolor 40% Beta-Glucans (including polysaccharides P and K)
Reishi (Ganoderma lucidum) 40% Beta-Glucans (1-3,{8}1-6 D- Beta Glucan, triterpenoids)
Nutricol®* EGCG, proanthocyanidins and resveratrol purified from Camellia sinensis (green tea) and Vitis vinifera (grape)
Bromelain enzyme complex (3,600 mcu)
MMIE contains a potent blend of extracts from six medicinal mushrooms recognized for their immune-enhancing effects, as well as a proprietary whole organic mushroom concentrated mycelia complex to further galvanize the immune response.
The Beneficial Effects of Mushrooms
A Preventative and Adjuvant Therapeutic Strategy Against Cancer. Jason A. Bush PhD* and Jason E. Watkin # *Cancer Research Center, The Burnham Institute, La Jolla, CA, 92037 USA # Biomedica Laboratories Inc, Duncan, BC, Canada.
The general frustration by the public on the lack of effective strategies for both the prevention and treatment of cancer has become increasingly apparent. Treatment for cancer is frequently an assault to the immune system. The side effects of conventional anti-cancer modalities, whether through the process of radiation or chemical treatment, is a general weakening of the body’s immune system resulting in immunosuppression that can significantly increase a patient’s risk for infection. In this patient population, infection can quickly progress to sepsis, septic shock, and death. Pneumonia and sepsis are common complications from chemotherapy and they are often lethal secondary effects that the modern cancer doctor, the oncologist, must face when ascribing treatment regimens. Why does this happen?
The targets of any anti-cancer treatment are the rapidly dividing cells within a tumor mass. The strategies used today try to selectively eradicate these rapidly dividing ‘rogue’ cells without adversely affecting other organs and tissues of the body. However, drug cocktails and radiation exposures are toxic to living cells. As a consequence to the toxic nature of treatment, other proliferating cells also become targets of therapy regimes. These include follicular hair cells and the immune cells, which manifest by hair loss and compromise of the body’s general defense mechanisms. The reality is such that, although treatments have improved over the past 50 years, the ‘magic bullet’ for cancer is still not available (except for some recent success with a specific kind of blood cancer).
These facts warrant the concept of boosting an individual’s immune system. This goal is validated by the current clinical practice, called immunotherapy, which consists of administering immune-modulating drugs often in combination with conventional chemo/radiotherapies to strengthen a patient’s tolerance to treatment. Furthermore, the spontaneous regression of some tumors in rare circumstances is usually explained as a phenomenon of the individual’s own immune system attacking the tumor burden. This is called the “host versus tumor response”. How and why this happens are questions basic research is trying to answer.
From a nutritional point-of-view, the supplementation of dietary compounds can significantly enhance the body’s innate response to foreign matter. ‘Immunoceuticals’ could provide some of the practical answers. An immunoceutical can be considered as any substance having immunotherapeutic potency when taken orally. The benefits of this pro-active approach are illustrated by the adage, “Eat to live, not live to eat.”
To combat the deficiencies in modern cancer treatment, biopharmaceutical companies and basic research facilities have taken two broad approaches: large-scale screening of natural compounds or a revisiting of the age-old remedies found in other cultures. Many large-scale, high-throughput systems are being utilized by the pharmaceutical industry as a means to screen for potential new drug candidates. These operations screen thousands of natural products derived from various plant and animal sources by mining diverse environments such as jungles of the rainforest to coral reefs in an attempt to find natural inhibitors of the cancer process or tumorigenesis. Alternatively, the age-old remedies common in other cultures of the world have been explored in greater depth as modes of potential therapeutic value. There are at least 250,000 species of plants out of which more than one thousand plants have been found to possess significant anti-cancer properties. A particular class of plants with well-documented properties that have received increased attention is the medicinal mushrooms and fungal fruiting bodies.
Plants and fungi have traditionally been the single most abundant source of lead compounds for the development of therapeutics by the biopharmaceutical industry while the pragmatic medicinal properties have been attributed to mushrooms for thousands of years. Mushroom extracts are widely distributed as nutritional supplements and heralded as beneficial for health. The complementary and alternative medicine professions have disseminated much of the current awareness regarding the utility of mushrooms. Mushroom and plant polysaccharides (sugars) are undergoing scientific analyses and development to prevent and treat cancer. Two classes of saccharides are the primary focus of investigations: (1) beta-glucan polysaccharides, as biological response modifiers for the adjuvant treatment of cancer; (2) oligosaccharin-related oligosaccharides, for the prevention of sun-induced skin cancer.
More than 50 mushroom species have yielded potential Immunoceuticals, which exhibit significant anti-cancer activity in experimental model systems. From this set, six promising species have emerged for further evaluation in human cancers. Importantly, all appear non-toxic and are well-tolerated. Some of the most impressive results have been obtained with orally administered extracts of Agaricus blazei in tumour-bearing animals where dramatic regression of tumours was demonstrated in multiple studies. Another extract referred to as Maitake D-Fraction from the common Maitake mushroom has shown promise in animal models and moderate efficacy in clinic. Small-scale clinical trials performed with beta-glucan extracts from Shiitake mushrooms, such as lentinan, have justified long-term U.S. clinical trials due to encouraging results seen with combination treatment in HIV patients, where immunosuppression is the causality of disease.
The recent rediscovery of the ancient Chinese herbal remedies derived from the fungus, Cordyceps sinensis, has prompted several preclinical trials in North America. These should support the growing number of clinical trials evaluating the respiratory, renal, hepatic, cardiovascular, immunologic, and anti-cancer effects already in human trials in the Far East. Two sugar-containing proteins from the medicinal mushroom, Coriolus versicolor, referred to as PSK (polysaccharide-K) and PSP (polysaccharide-P) have demonstrated the most promise. These protein-bound polysaccharides have been used as a chemoimmunotherapy agent in the treatment of cancer in Asia for over 30 years. PSK and PSP were found to boost immune cell production, ameliorate chemotherapy symptoms, and enhance tumour infiltration by immune cells. Yet another powerful new candidate mushroom, Reishi, has the ability to inhibit the proliferation of highly invasive cancer cells in cultured conditions. Other beta-glucans that prime one’s natural killer cells for antibody dependent cell-mediated cytotoxicity are approaching clinical trials. The oligosaccharides found in many of these species can reduce the production of immunosuppressive hormones caused during sunburns, and therefore, support a role as preventative agents of environmental skin cancer.
From these examples, it is clear that increasing the ability of the host to defend itself from tumor progression is of paramount importance for the control of cancer. The various whole mushrooms and isolated medicinal mushroom compounds still require more in-depth pharmacologic and mechanistic studies with further definition of eucopeni-function relationships before they are ready for large-scale clinical trials in the West. However, the precedence of toxicological studies is well-established now in Asia and controlled research, including open-label and double-blinded rather than empirical results, is underway. The general conclusions from the literature on the consumption of medicinal mushrooms support a significantly improved quality of life and enhanced immune status. Their extremely high tolerability and compatibility with conventional surgery and therapy makes them excellent choices for cancer management regimens. By understanding the manner through which medicinal mushrooms work, new doors may open in the development of novel strategies for the treatment of human malignancies. This is best exemplified with the early success of a new class of anti-cancer drug derived from mushroom.
High Dose Melatonin
Melatonin is a hormone produced by the pineal gland in our brain, with neurotransmitter modulatory activity. Most of us are aware that melatonin is responsible for promoting sleep, but most are unaware that melatonin can directly kill many different types of cancer cells. It is a naturally produced cytotoxin, which can induce tumor cell death (apoptosis). In instances where the tumor has already established itself in the body, melatonin has been shown to inhibit the tumor’s growth rate.
Melatonin exhibits natural oncostatic activity and inhibits cancer cell growth. In patients in whom cancer already has become a noticeable physical burden and produces overt symptoms, melatonin has been shown to alleviate numerous cancer symptoms and to inhibit development of new tumor blood vessels (tumor angiogenesis), which in turn inhibits the cancer from spreading further (metastasis). Melatonin can retard tumor metabolism and development by lowering the body temperature; it is a natural inducer of hypothermia. Furthermore, as an inducer of antioxidants and itself a weak preventive antioxidant, melatonin hinders tumor cells from participating in free radical damage to normal cells and consequently limits oxidative damage to DNA, lipids, amino acids, and proteins.
Summary of Studies Using Melatonin Lissoni’s Phase II Randomized Clinical Trial Results
One-Year Survival
Tumor Type Patient Number Basic Therapy Melatonin Dose Melatonin Placebo Level Of Significance
Metastatic Non- Small-Cell Lung 100 Chemotherapy 20 mg 5-year survival 6% 5-year survival 0% N/A
Metastatic Non- Small-Cell Lung 63 Supportive Care Only 10 mg 5-year survival 6% Under 1% <0.05
Glioblastoma 30 Conventional Radiotherapy 10 mg 43% Under 1% < 0.05
Metastatic Breast 14 Tamoxifen 20 mg 64% 36% < 0.01
Brain Metastases 50 Conventional Radiotherapy 20 mg 38% 12% <0.05
Metastatic Colorecta 50 IL-2 40 mg 36% 12% <0.05
Metastatic Non- Small-Cell Lung 60 IL-2 40 mg 24% 19% <0.05
Squalamine Extract
Anti-Angiogenesis
Squalamine was originally discovered in the tissues of the dogfish shark and is part of a class of naturally occurring, pharmacologically active small molecules known as “aminosterols.” Squalamine has exhibited reproducible anti-angiogenic properties in a number of in vitro and in vivo assays, including eye disease and cancer models, across multiple independent laboratories.Cancer
Squalamine may be potentially useful as an anti-angiogenic therapy for some types of cancer. From research done in cancer, including Phase I and II clinical trials, a significant safety database for squalamine as a single agent and in combination with other agents has been compiled. It appears that squalamine is less toxic and better tolerated than other therapies, not only chemotherapy, but also approved anti-angiogenics. Squalamine continues to be evaluated in Phase 2 clinical studies for the treatment of solid tumors. Specifically, clinical studies have been performed in prostate cancer and non-small cell lung cancer (NSCLC) to evaluate intravenously administered squalamine in combination with leading chemotherapeutics in each indication. Phase 2 trials in ovarian cancer have also been conducted, as described below. In November 2001, a Phase 2b trial in non-small cell lung cancer investigated weekly dosing of squalamine in combination with the leading chemotherapeutics. In November 2002, a $1.1 million award was granted by the United States Department of Defense, Army Medical Research and Materiel Command (USAMRMC) to the University of Chicago, School of Medicine for the first clinical trial of squalamine in the treatment of prostate cancer. The trial is designed as an open-label randomized study to evaluate the activity and tolerability of squalamine in conjunction with anti-androgen therapy in patients undergoing radical prostatectomy. Up to 132 patients will receive weekly dosing of squalamine (100 mg/m2) for either 6 or 12 weeks. The study continues to enroll patients. In May 2002, Phase 2 trials in recurrent advanced ovarian cancer revealed the following: 35% of evaluable patients (9 of 26) had an objective response to the study drug regimen of squalamine and carboplatin. Best response to therapy has included five complete responses, and four partial responses. The U.S. Food and Drug Administration granted squalamine Orphan Drug designation for the treatment of ovarian cancer in 2001. Also, in May 2002, positive final results for squalamine in its Phase 2a NSCLC clinical trial were announced. The median survival time for all patients enrolled in the study was 10.0 months (95% confidence interval, 6.6 to 12.3 months). The median survival time for patients receiving the squalamine dose of 300 mg/m2/day was 8.5 months (95% C.I. 6.6 to 17.8 months). The median time to progression was 4.4 months (95% C.I. 3.1 to 6.9 months) for all study patients, 5.5 months for patients in the 300 mg/m2/day group (95% confidence interval 3.2 to 9.4 months). On June 5, 2004, at the On June 5, 2004, at the 40th Annual Meeting of the American Society of Clinical Oncology (ASCO), updated interim safety and efficacy results from squalamine were presented in a Phase IIB NSCLC clinical trial. This multi-center randomized study enrolled 45 stage IIIB or stage IV advanced lung cancer patients who were to receive weekly dosing of squalamine, combined with weekly chemotherapy of carboplatin and paclitaxel. All 45 patients were evaluated for safety. Overall, the combined drug regimen was well tolerated. Two patients were withdrawn for intercurrent illnesses before receiving any study medication. Of the 43 patients receiving study medications, 21 received a weekly dose of 100 mg/m2, and 22 received a weekly dose of 200 mg/m2 of squalamine. Forty-one patients were evaluable for efficacy. Objective responses occurred in 24% of the patients (10 of 41; 1 complete and 9 partial responses). An objective response is defined as a 50% or greater reduction in tumor size, measured bi-dimensionally by CT scan, lasting 4 weeks, with no new lesions appearing, as rated by the investigators and radiologists. In comparison, the objective response rate was 27% in a prior Phase IIA NSCLC study dosing squalamine daily for five days every three weeks, in combination with carboplatin and paclitaxel every three weeks. In summary, the one year survival rate is 22%, with a 72% overall response rate that include one durable complete response with squalamine combination therapy. Thirteen patients remain alive while progression and survival statistics continue to mature.Squalamine and cisplatin block angiogenesis and growth of human ovarian cancer cells with or without HER-2 gene over-expression. Dan Li1, Jon I Williams2 and Richard J Pietras1, 1UCLA School of Medicine, Department of Medicine, Division of Hematology-Oncology and Jonsson Comprehensive Cancer Center, Los Angeles, California, CA 90095, USA, 2Genaera Corporation, Plymouth Meeting, Pennsylvania, PA 19462, USA. Correspondence to: RJ Pietras, Department of Medicine, Division of Hematology-Oncology, 10833 Le Conte Ave., 11-934 Factor Bldg., Los Angeles, CA 90095-1678, USA
Abstract
Angiogenesis is important for growth and progression of ovarian cancers. Squalamine is a natural anti-angiogenic sterol, and its potential role in treatment of ovarian cancers with or without standard cisplatin chemotherapy was assessed. Since HER-2 gene over-expression is associated with cisplatin resistance in vitro and promotion of tumor angiogenesis in vivo, the response of ovarian cancer cells with or without HER-2 gene over-expression to squalamine and cisplatin was evaluated both in tumor xenograft models and in tissue culture. Ovarian cancer cells with or without HER-2 over-expression were grown as subcutaneous xenografts in nude mice. Animals were treated by intra-peritoneal injection with control vehicle, cisplatin, squalamine or cisplatin combined with squalamine. At the end of the experiment, tumors were assessed for tumor growth inhibition and for changes in microvessel density and apoptosis. Additional in vitro studies evaluated effects of squalamine on tumor and endothelial cell growth and on signaling pathways in human endothelial cells. Profound growth inhibition was elicited by squalamine alone and by combined treatment with squalamine and cisplatin for both parental and HER-2-overexpressing ovarian tumor xenografts. Immunohistochemical evaluation of tumors revealed decreased microvessel density and increased apoptosis. Although HER-2-overexpressing tumors had more angiogenic and less apoptotic activity than parental cancers, growth of both tumor types was similarly suppressed by treatment with squalamine combined with cisplatin. In in vitro studies, we found that squalamine does not directly affect proliferation of ovarian cells. However, squalamine significantly blocked VEGF-induced activation of MAP kinase and cell proliferation in human vascular endothelial cells. The results suggest that squalamine is anti-angiogenic for ovarian cancer xenografts and appears to enhance cytotoxic effects of cisplatin chemotherapy independent of HER-2 tumor status. Oncogene (2002) 21, 2805-2814. DOI: 10.1038/sj/onc/1205410 To assess the antitumor efficacy of squalamine in human ovarian cancer, a phase II clinical study was performed by Davidson et al. (52). On recruiting 33 patients with stage III or stage IV ovarian cancer who were resistant or refractory to platinum-based chemotherapy, squalamine was administered with carboplatin as a 5-day continuous infusion at a dose of 200 mg/m2/day. Average treatment time was 81 days. Response data have been reported for 22 patients, and, among this group, eight patients had an objective clinical response. Major toxicity reported in this study among three patients was grade 4 thrombocytopenia, anemia, eucopenia, myalgia or asthenia, symptoms often associated with carboplatin chemotherapy. Additional patients were enrolled in the study, but the final data remain to be presented (52). Nonetheless, these results suggest that squalamine may be a significant addition to current treatment options for patients with advanced refractory ovarian cancers. Based on currently-available information on the potential antitumor efficacy of squalamine in ovarian cancer, the antiangiogenic steroid has been designated an ‘orphan drug’ candidate for future therapeutic development in ovarian malignancy, a group for whom new treatment alternatives are urgently needed. June 4, 2002 Squalamine Yields Positive Results in NSCLC. Scientists from Genaera announced positive final results for squalamine in a phase II non-small cell lung cancer (NSCLC) clinical trial. Dr. Joan Schiller of the University of Wisconsin was the lead researcher. The multicenter open-label study investigated the preliminary efficacy and safety of squalamine used with first-line standard chemotherapy of carboplatin (Paraplatin) and paclitaxel (Taxol) in patients with stage IIIB or IV advanced disease. The phase Iia NSCLC trial initially enrolled 18 patients with an escalating dose of squalamine from 100 mg/m/day to 400 mg/m/day. Researchers then enrolled 27 patients in a second portion of the study at 300 mg/m/day of squalamine. The patients received up to 6 cycles of carboplatin and paclitaxel every 3 weeks, immediately followed by 5 daily treatments of squalamine every 3 weeks.For all patients enrolled in the study at all squalamine doses, 27% experienced an objective response. Objective responses were seen in 29% of patients receiving of 300 mg/m/day of squalamine for one or more cycles of therapy; an appropriate historical benchmark objective response rate for this group of patients treated with carboplatin and paclitaxel alone was 17%, and the median survival time for all patients enrolled was 10.0 months. The median survival time for patients receiving the squalamine dose of 300 mg/m/day was 8.5 months; again, the historical benchmark objective median survival for this group treated with carboplatin and paclitaxel alone was 8.1 months. The median time to progression was 4.4 months for all patients, 5.5 months for patients in the 300 mg/m/day group, and 3.1 months in the comparison data. An ongoing phase Iib study in NSCLC patients is designed to evaluate 90 patients with first-line therapy of 100 mg/m or 200 mg/m of squalamine weekly used with weekly carboplatin and paclitaxel.
Acetyl L Carnitine
Efficacy of l-carnitine administration on fatigue, nutritional status, oxidative stress, and related quality of life in 12 advanced cancer patients undergoing anticancer therapy.Giulia Gramignano M.D., Maria Rita Lusso M.D., Clelia Madeddu M.D., Elena Massa M.D., Roberto Serpe B.Sc., Laura Deiana M.D., Giovanna Lamonica M.D., Mariele Dessì M.D., Carla Spiga M.D., Giorgio Astara M.D., Antonio Macciò M.D. and Giovanni Mantovani M.D. Department of Medical Oncology, University of Cagliari, Monserrato, Italy Received 19 April 2005; accepted 15 June 2005. Available online 2 February 2006
Fatigue is a multidimensional symptom that is described in terms of perceived energy, mental capacity, and psychological status: it can impair daily functioning and lead to negative effects on quality of life. It is one of the most common side effects of chemotherapy and radiotherapy. In recent studies, l-carnitine (LC) supplementation has been demonstrated to be able to improve fatigue symptoms in patients with cancer.
In the present study we tested the efficacy and safety of LC supplementation in a population of patients who had advanced cancer and developed fatigue, high blood levels of reactive oxygen species, or both. As outcome measures we evaluated fatigue and quality of life in relation to oxidative stress, nutritional status, and laboratory variables, mainly levels of reactive oxygen species, glutathione peroxidase, and proinflammatory cytokines. From March to July 2004, 12 patients who had advanced tumors (50% at stage IV) at different sites were enrolled (male-to-female ratio 2:10, mean age 60 y, range 42–73). Patients were only slightly anemic (hemoglobin 10.9 g/dL) and hemoglobin levels did not change after treatment. LC was administered orally at 6 g/d for 4 wk. All patients underwent antineoplastic treatment during LC supplementation.
Results
Fatigue, as measured by the Multidimensional Fatigue Symptom Inventory—Short Form, decreased significantly, particularly for the General and Physical scales, and for quality of life in each subscale of quality of life in relation to oxidative stress. Nutritional variables (lean body mass and appetite) increased significantly after LC supplementation. Levels of reactive oxygen species decreased and glutathione peroxidase increased but not significantly. Proinflammatory cytokines did not change significantly.Shark Liver Oil
One of the primary ingredients in Shark Liver Oil are the “alkylglycerols.” New findings are validating the disease prevention and treatment effects of alkylglycerols, suggesting that shark liver oil extract may one day be integrated into mainstream medicine. Alkylglycerols were first isolated by a physician in Sweden named Dr. Astrid Brohult. Dr. Brohult was treating children with leukemia, with little success. Because white blood cells are produced in the bone marrow, she started to feed the sick children bone marrow from calves. The result of this bone marrow feeding was a marked improvement in the children’s immune systems and white blood cell counts. Unfortunately, Dr. Brohult could not get the children to eat enough bone marrow to sustain these results. So Dr. Brohult set out to find the active ingredient in bone marrow and isolate it. With the help of her husband Dr. Sven Brohult, it was determined that alkylglycerols were responsible for the immune system enhancing effects. Were there any other sources? Yes! In fact, these same compounds are found in the livers of cold-water sharks, like the Greenland Shark. The shark in general has gained a lot of popularity because cancer occurrence is very rare in sharks. The existence of alkylglycerols in their liver may be one reason for the natural immunity to cancers.Shark Liver Oil and Cancer
The biologic effects of shark liver oil include stimulation of blood leukocyte and thrombocyte production as well as the activation of macrophage and anti-tumor activity. Other effects include the ability to protect against radiation damage during radiation therapy for various types of cancer. Alkylglycerols act as a powerful immune system booster against infectious disease and are what help give nursing animals, including breast-fed babies, protection against infection until their own immune systems can fully develop. In a study published in the Journal of Cell Physiology ( February 1999), researchers studied the cell differentiation-promoting potential of a particular type of alkylglycerols on human colon cancer cells. The scientists wanted to observe the ability of alkylglycerols to change the biological makeup of human colon cancer cells. Alkylglycerols were shown to “. . . . promote a more benign or differentiated phenotype in colon cancer cells.” Treatment of the cancer cells with alkylglycerols resulted in a reduction of cellular proliferation and a reduced capacity for cellular invasion. In other words, alkylglycerols led to lowered cancer cell reproduction and a reduced ability of the cancer cells to invade healthy cells. The authors concluded that alkylglycerols possess both cancer preventative properties, as well as cancer treatment effects. In a study published in the Journal of Alternative & Complementary Medicine (Spring 1998), researchers extolled the many biologic actions of shark liver oil alkylglycerols. It was pointed out that shark liver oil has been around for 40 years and has been used as both a preventative and therapeutic agent. Not only have alkylglycerols been used to treat leukemia, as in the case of the children in Sweden, they have also been used to prevent radiation sickness stemming from radiation cancer treatments. Furthermore, the high level of alkylglycerols that exist naturally within any given tumor cell has lead scientists to postulate that this is may be an apparent attempt of the body to control cell growth. In another study referred to in this paper, researchers found that the activation of protein kinase C, an essential step in cancer cell growth, can actually be stopped or inhibited by alkylglycerols. In addition, it’s been suggested that alkylglycerols directly act on the macrophages (large immune cells that gobble up cancer cells). Overall, alkylglycerols are able to stimulate the macrophage to secrete over 50 substances concerned directly or indirectly with the immune system. Some of these substances, the interleukins, are powerful immune system fighters that interact with lymphocytes.Biological Action and Clinical Application of Shark Liver Oil
Pol Merkur Lekarski. 2006; 20(119):598-601 Lewkowicz N; Lewkowicz P; Kurnatowska A; Tchórzewski H Uniwersytet Medyczny w Lodzi, Zak?ad Periodontologii I Chorób B?ony Sluzowej Jamy Ustnej. natalewk@wp.plFish oils contain several active compounds that modify cell activity and influence various functions of the body. Shark liver oils are rich in alkylglycerols and squalene, but contain relatively low amounts of n-3 polyunsaturated fatty acids. Alkylglycerols may control immune response possibly throw modification of platelet activating factor (PAF) and diacylglycerol (DAG) production. Squalene enhances antigen presentation and induction of inflammatory response. Moreover, alkylglycerols and squalene have antitumour activity, that is possibly based on different mechanisms, ie., induction of apoptosis of neoplastic cells, suppression of signal transduction, inhibition of angiogenesis and promoting of transmembrane transport of cytotoxic agents. Shark liver oil has been found to be useful in treatment of conditions resulted from inadequate immune response, and in adjunctive treatment of several types of cancer.
Cytostatic and cytotoxic effects of alkylglycerols (Ecomer) Krotkiewski M; Przybyszewska M; Janik P Sahlgrenska Academy, Göteborg University, Gothenburg Institute of Clinlcal Neuroscience, Göteborg, Sweden.
Background
Shark liver oil, with a standardized concentration of alkylglycerols and their methoxyderivates, has been widely used in Scandinavian countries as complementary medicine in the treatment of different forms of cancer. The aim of our study was to verify the hypothesized antiproliferative effect of alkylglycerols in different human cancer cell lines. MATERIAL/METHODS: The plating efficiency method was used to assay the effect of alkylglycerols on the plating efficiency of human ovarian carcinoma (OVP-10), mammary carcinoma (MCF-7), and prostate cancer (DU-145, PC-3 and Pca-2b) cell lines. Tumor colonies containing more than 20 cells were scored as positive. Flow cytometry was applied to identify necrotic vs. apoptotic mode of cell death. The cells were exposed to Ecomer shark liver oil containing 20% alkylglycerols and 3% methoxyderivates in a dose of 0.1 mg/ml, up to a concentration corresponding to LD-50. Apoptotic and necrotic cells were stained with Anexin V and propidium iodine respectively.Results
The prostate cells from DU-145, PC-3 and Pca-2B showed a dramatic reduction in the colony number even after relatively small doses of 0.5 and 0.1 mg/ml medium. Flow cytomery showed an increased percentage of apoptotic cells of ovarian and prostate carcinoma, while mammary carcinoma cells showed predominantly necrotic cells after exposure to Ecomer.Conclusions
The alkylglycerols and their methoxyderivates present in Ecomer shark liver oil showed a clear apoptotic/necrotic effect on human prostate and mammary carcinoma cell lines.Green Tea Extract has Potential as an Anti-Cancer Agent
A new study on bladder cancer cells lines shows that green tea extract has potential as an anti-cancer agent, proving for the first time that it is able to target cancer cells while leaving healthy cells alone.The study, published in the Feb. 15, 2005 issue of the peer-reviewed journal Clinical Cancer Research, also uncovered more about how green tea extract works to counteract the development of cancer, said JianYu Rao, a Jonsson Cancer Center member, an associate professor of pathology and laboratory medicine and the study’s senior author.
“Our study adds a new dimension in understanding the mechanisms of green tea extract,” Rao said. “If we knew exactly how it works to inhibit the development of cancer, we could figure out more precisely which bladder cancer patients might benefit from taking it.”
Numerous epidemiologic and animal studies have suggested that green tea extract provides strong anti-cancer effects in several human cancers, including bladder cancer. It has been shown to induce death in cancer cells, as well as inhibiting the development of an independent blood supply that cancers develop so they can grow and spread.
In the UCLA study, which brought together researchers from UCLA’s Jonsson Cancer Center, School of Public Health, Center for Human Nutrition and the departments of Pathology and Laboratory Medicine, Surgery, Urology and Epidemiology, scientists were able to show that green tea extract interrupts a process that is crucial in allowing bladder cancer to become invasive and spread to other areas of the body.
Green tea extract affects actin remodeling, an event associated with cell movement. When a human moves, the muscles and skeletal structure operate together to facilitate that movement. For cancer to grow and spread, the malignant cells must be able to move. The cell movement depends on actin remodeling, which is carefully regulated by complex signaling pathways, including the Rho pathway. When actin remodeling is activated, the cancer cells can move and invade other healthy cells and eventually other organs. By inducing Rho signaling, the green tea extract made the cancer cells more mature and made them bind together more closely – a process called cell adhesion. Both the maturity of the cells and the adhesion inhibited the mobility of the cancer cells, Rao said.
“In effect, the green tea extract may keep the cancer cells confined and localized, where they are easier to treat and the prognosis is better,” Rao said. “Cancer cells are invasive and green tea extract interrupts the invasive process of the cancer.” Bladder cancer is the fifth most common cancer in the United States, with about 56,000 new cases diagnosed each year. About half of all bladder cancers are believed to be related to cigarette smoking. Without a reliable, non-invasive way to diagnose the disease, bladder cancer can be difficult to detect in the early, most treatable stages. When not found early, the tumors can be aggressive, and more than half of patients with advanced cancers experience recurrences.
UCLA researchers currently are seeking hundreds of former smokers who have had bladder cancer for a clinical trial studying whether green tea extract prevents recurrence – one of the first studies in the country to test the agent on cancer patients. The study is part of a comprehensive program funded by the National Cancer Institute and designed to prevent the recurrence and progression of smoking-related bladder cancer. In addition to the trial, the program seeks to develop new biomarker tests to help predict who will get bladder cancer, discover the molecular profile of the disease to identify those most at risk and create a tumor bank to aid research.
Rao cautioned that his study was conducted in a carefully controlled cell line environment and that more research needs to be done to discover exactly how green tea extract functions as a cancer fighter. The next phase of his research will analyze urine from bladder cancer patients to determine which subset of patients would benefit most from taking green tea extract. Researchers will be looking for specific biomarkers associated with actin remodeling and activation of the Rho signaling pathway. “We’re hoping the results from these studies will tell us who will best benefit from the agent,” Rao said, adding that the basic research he is doing and the clinical trial on bladder cancer patients will provide scientists with vital information from both ends the research continuum, an example of bench-to-bedside-and-back-again science.
“I think this publication further supports the potential role of green tea in the prevention and treatment of bladder cancer,” said Dr. Robert Figlin, a UCLA professor of hematology/oncology and urology and a principal investigator for the human studies. “In the end, both studies will help us achieve our goal – to decrease bladder cancer occurrence and develop molecular profiles that tell us who is most at risk.”
UCLA’s Jonsson Comprehensive Cancer Center is composed of more than 240 cancer researchers and clinicians engaged in cancer research, prevention, detection, control and education. One of the nation’s largest comprehensive cancer centers, the JCCC is dedicated to promoting cancer research and applying the results to clinical situations. In 2004, the Jonsson Cancer Center was named the best cancer center in the western United States by U.S. News & World Report, a ranking it has held for five consecutive years.
Methyl Selenocysteine
Although Methyl-selenocysteine is one of the most biologically active, and cancer inhibitory and preventive selenium compounds, the less active Seleno-methionine and selenite are the selenium forms currently available in the majority of nutritional supplements.It has become increasingly evident that dietary Se plays a significant role in reducing the incidence of lung, colorectal and prostate cancer in humans. Different forms of Se vary in their chemopreventative efficacy, with Se-methylselenocysteine being one of the most potent. Interestingly, the Se accumulating plant Astragalus bisulcatus (Two-grooved poison vetch) contains up to 0.6% of its shoot dry weight as Se-methylselenocysteine. The ability of this Se accumulator to biosynthesize Se-methylselenocysteine provides a critical metabolic shunt that prevents selenocysteine and selenomethionine from entering the protein biosynthetic machinery. Such a metabolic shunt has been proposed to be vital for Se tolerance in A. bisulcatus. Utilization of this mechanism in other plants may provide a possible avenue for the genetic engineering of Se tolerance in plants ideally suited for the phytoremediation of Se contaminated land. Here, we describe the overexpression of a selenocysteine methyltransferase from A. bisulcatus to engineer Se-methylselenocysteine metabolism in the Se non-accumulator Arabidopsis thaliana (Thale cress).
Results
By over producing the A. bisulcatus enzyme selenocysteine methyltransferase in A. thaliana, we have introduced a novel biosynthetic ability that allows the non-accumulator to accumulate Se-methylselenocysteine and γ-glutamylmethylselenocysteine in shoots. The biosynthesis of Se-methylselenocysteine in A. thaliana also confers significantly increased selenite tolerance and foliar Se accumulation.Conclusion
These results demonstrate the feasibility of developing transgenic plant-based production of Se-methylselenocysteine, as well as bioengineering selenite resistance in plants. Selenite resistance is the first step in engineering plants that are resistant to selenate, the predominant form of Se in the environment.Selenium
Selenium is an essential nutrient for animals, microorganisms and some other eukaryotes. While Se deficiency is rare in the US, it does occur in several low Se parts of the world such as China, and can lead to heart disease, hypothyroidism and a weakened immune system. The toxic effects of excess Se have been known for some time. Short-term consumption of high levels of Se may cause nausea, vomiting, and diarrhea, whereas chronic consumption of high concentrations of Se compounds can result in a disease called selenosis. Only one form of Se, selenium sulfide, has been implicated as a carcinogen. The recognition of Se bioaccumulation and resulting wildlife toxicity at Kesterson reservoir in California and other sites has resulted in a surge of interest in phytoremediation of Se. Selenium in the environment can be the result of either natural geological processes or human activities. The USGS has identified 160,000 miles2 of land in the western US enriched in Se from natural processes that is susceptible to irrigation-induced Se contamination, including 4,100 miles2 of land currently irrigated for agriculture. Selenium pollution can also arise from various industrial and manufacturing processes including procurement, processing, and combustion of fossil fuels, and mining.Interestingly, in the last decade it has become increasingly evident that Se also has potential health benefits. Anticarcinogenic activities of specific organic forms of Se against certain types of cancer have been demonstrated. In a long term, double-blind study, supplemental dietary Se was associated with significant reductions in lung, colorectal and prostate cancer in humans [3]. Other studies have also demonstrated the chemoprotective effects of Se against breast, liver, prostate, and colorectal cancers in model systems. Importantly, there is a great deal of variation in the efficacy of different Se compounds against cancer. Numerous studies have demonstrated the efficacy of Se-methylselenocysteine (MeSeCys) in preventing mammary cancer in rat model systems, and importantly, MeSeCys has been shown to be twice as active as Se-methionine (the primary component of Se-yeast supplements) in preventing the development of mammary tumors in rats. Furthermore, MeSeCys in both garlic and broccoli has also been shown to be more effective than either Se-methionine (SeMet) in yeast, or broccoli supplemented with selenite, at reducing both the incidence of mammary and colon cancer in rats. This nonprotein seleno amino acid is produced in certain plants including members of the Brassica and Allium genera, and in Se accumulating plants such as Astragalus bisulcatus. While the specific mechanism for the anticancer activity of Se has not been fully elucidated, multiple studies have demonstrated the ability of Se to affect the cell cycle and induce apoptosis in cancer cell lines. There is also evidence that Se may inhibit tumor angiogenesis. Both of these activities would inhibit progression of early cancerous lesions.
Plants primarily take up Se as selenate or selenite [38], which is then metabolized, via the sulfur assimilation pathway, resulting in the production of selenocysteine, SeMet and other Se analogues of various S metabolites, as reviewed by Ellis and Salt (2003). The nonspecific incorporation of seleno amino acids into proteins is thought to contribute to Se toxicity [40]. One proposed mechanism of Se tolerance in plants is the specific conversion of potentially toxic seleno amino acids into nonprotein derivatives such as MeSeCys. Some Brassica and Allium species, when grown in Se enriched medium, can accumulate 0.1–2.8 μmol g-1 dry weight MeSeCys or its functional equivalent γ-glutamylmethylselenocysteine (γGluMeSeCys). However, certain specialized Se accumulating plants, such as A. bisulcatus, accumulate up to 68 μmol g-1 dry weight Se (6000 μg g-1 dry weight), of which 90–95% is MeSeCys in young leaves.
Selenocysteine methyltransferase (SMT), the enzyme responsible for the methylation of selenocysteine to MeSeCys in A. bisulcatus, has recently been cloned and characterized [47]. The availability of such genetic material opens a practical avenue for the development of plants with an enhanced ability to biosynthesize MeSeCys. Such plants would be expected to not only be more resistant to Se, a valuable trait for phytoremediation of Se contaminated land, but also provide a plant based source of the anticarcongenic compound MeSeCys. Here, we describe the successful use of A. bisulcatus genetic material to engineer MeSeCys metabolism in the Se non-accumulator A. thaliana. By over-producing the A. bisulcatus enzyme SMT in A. thaliana, we have introduced a novel biosynthetic ability that has increased the concentration of MeSeCys and its functional derivative γGluMeSeCys, from essentially non-detectable levels in the leaves of wild-type A. thaliana up to 3.9 μmol g-1 dry weight in shoots.
Selenium
Monomethylated selenium inhibits growth of LNCaP human prostate cancer xenograft accompanied by a decrease in the expression of androgen receptor and prostate-specific antigen (PSA). Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.Objectives
Epidemiological studies and prevention trials suggest selenium is a promising preventive agent for prostate cancer. Selenium-containing compounds inhibited the growth of prostate cancer cell lines including androgen sensitive LNCaP and androgen insensitive DU145 and PC3 cells in vitro. Previous study revealed a novel mechanism of selenium action in which selenium (methylseleninic acid (MSA)) markedly reduced androgen receptor (AR) signaling in prostate cancer cells, suggesting that selenium might act as an antiandrogen, which could serve as a therapeutic agent for prostate cancer. In this study, we tested whether selenium (methylselenocysteine (MSC)) affects tumor growth of human prostate cancer cells by targeting AR signaling in vivo. METHODS: Prostate tumor xenografts were established in nude mice by co-inoculating LNCaP cells with Matrigel. The mice-bearing tumors were treated with or without MSC (100 microg/mouse/day) via intraperitoneal injection for 2 weeks. The effect of MSC on tumor growth, AR, and prostate-specific antigen (PSA) expression was examined.Results
Methylselenocysteine (MSC) significantly inhibited LNCaP tumor growth (P < 0.05). AR expression in tumor tissues and serum PSA levels were considerably decreased in MSC-treated mice compared to the vehicle controls.Conclusions
Pharmacological dose of MSC inhibits the growth of LNCaP human prostate cancer in vivo accompanied by a decrease in the expression of AR and PSA. These findings suggest that selenium (MSC) can serve as a therapeutic agent aimed at disruption of AR signaling for prostate cancer. Copyright 2005 Wiley-Liss, Inc.Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group.
L. C. Clark, G. F. Combs Jr, B. W. Turnbull, E. H. Slate, D. K. Chalker, J. Chow, L. S. Davis, R.A. Glover, G. F. Graham, E. G. Gross, A. Krongrad, J. L. Lesher Jr, H. K. Park, B. B. Sanders Jr, C. L. Smith and J. R. Taylor Arizona Cancer Center, College of Medicine, University of Arizona, Tucson, USA
Objective
To determine whether a nutritional supplement of selenium will decrease the incidence of cancer.Design
A multicenter, double-blind, randomized, placebo-controlled cancer prevention trial.Setting
Seven dermatology clinics in the eastern United States. PATIENTS: A total of 1312 patients (mean age, 63 years; range, 18-80 years) with a history of basal cell or squamous cell carcinomas of the skin were randomized from 1983 through 1991. Patients were treated for a mean (SD) of 4.5 (2.8) years and had a total follow-up of 6.4 (2.0) years.Interventions
Oral administration of 200 microg of selenium per day or placebo. MAIN OUTCOMEMeasures
The primary end points for the trial were the incidences of basal and squamous cell carcinomas of the skin. The secondary end points, established in 1990, were all-cause mortality and total cancer mortality, total cancer incidence, and the incidences of lung, prostate, and colorectal cancers.Results
After a total follow-up of 8271 person-years, selenium treatment did not significantly affect the incidence of basal cell or squamous cell skin cancer. There were 377 new cases of basal cell skin cancer among patients in the selenium group and 350 cases among the control group (relative risk [RR], 1.10; 95% confidence interval [CI], 0.95-1.28), and 218 new squamous cell skin cancers in the selenium group and 190 cases among the controls (RR, 1.14; 95% CI, 0.93-1.39). Analysis of secondary end points revealed that, compared with controls, patients treated with selenium had a nonsignificant reduction in all-cause mortality (108 deaths in the selenium group and 129 deaths in the control group [RR; 0.83; 95% CI, 0.63-1.08]) and significant reductions in total cancer mortality (29 deaths in the selenium treatment group and 57 deaths in controls [RR, 0.50; 95% CI, 0.31-0.80]), total cancer incidence (77 cancers in the selenium group and 119 in controls [RR, 0.63; 95% CI, 0.47-0.85]), and incidences of lung, colorectal, and prostate cancers. Primarily because of the apparent reductions in total cancer mortality and total cancer incidence in the selenium group, the blinded phase of the trial was stopped early. No cases of selenium toxicity occurred.CONCLUSIONS
Selenium treatment did not protect against development of basal or squamous cell carcinomas of the skin. However, results from secondary end-point analyses support the hypothesis that supplemental selenium may reduce the incidence of, and mortality from, carcinomas of several sites. These effects of selenium require confirmation in an independent trial of appropriate design before new public health recommendations regarding selenium supplementation can be made.Vitamin K
Vitamin K is one of the fat-soluble vitamins, yet it has received far less attention from the supplement-consuming public than its more famous “cousins” A, D and E. Discovered in 1929 in Denmark, vitamin K was thought to be useful only to promote normal blood coagulation, as part of the complex “clotting cascade” that keeps us from bleeding to death from cuts or broken internal blood vessels. Vitamin K even got its name from the first letter of the Danish word koagulation. Research over the last 25 years has gradually given a new and more expanded view of the role of K. It is now known to be essential for bone health, and may also be important to prevent atherosclerosis and calcified arterial plaque. It may also be crucial for brain health. The term “vitamin K” refers to a family of related compounds, whose members all have the basic “clotting power” of K (Fig. 1). Vitamin K1 (phylloquinone or phytonadione) is formed by plants, and is the main dietary source of K. A diet high in green vegetables such as kale, spinach, broccoli, lettuce and cabbage might provide hundreds of micrograms of K1 per day.1 The FDA’s RDA (recommended daily allowance) for K is 80 mcg per day. Vitamin K2 (menaquinones, menatetrenone) refers to a group of related compounds, menaquinones 2-9. Some menaquiones are produced by our gut bacteria, but the evidence suggests this K2 is poorly absorbed, if at all.2,3 Humans and animals normally convert some ingested K1 to menaquinone-4 (MK4), also called menatetrenone.4,5 This is the specific mammalian K2. Vitamin K3 (menadione) has the same naphthoquinone “head” as K1 and K2, but lacks a side chain. K3 is a synthetic form of K.1.K and Bone Health
Studies conducted with humans and animals over the past 20 years have gradually made it clear that vitamin K is essential to optimal bone health, especially among post-menopausal women and elderly men. Yet it is the K2 form that has been shown to be the bone builder. Kaneki and colleagues in Japan compared K2 levels in the blood of 24 women with osteoporotic vertebral fractures and 36 elderly women without fractures. Serum levels of K1 were virtually identical in both groups, yet serum levels of MK7 (a K2 form found in soy natto, a popular Japanese food) were twice as high in the nonfracture group compared to the fracture group.6. Japanese women tend to suffer much less osteoporosis fractures than Western women. A recent study found that fracture incidence within Japan was strongly correlated to natto intake and blood serum levels of MK7. MK7 levels were 5.26 ng/mL in Tokyo women, 1.22 in Hiroshima, and 0.37 in British women. Natto consumption is high in Tokyo, lower in Hiroshima, and non-existent in Britain. The authors concluded: “A statistically significant inverse correlation was found between incidence of hip fractures in women and natto consumption [chief dietary source of MK7] in each prefecture [district] throughout Japan.”7 In other words, the more natto, the more MK7, and the fewer fractures.Menatetrenone (K2) and Bone Health
The Japanese have pioneered the use of K2 (menatetrenone, or MK4) supplements to treat osteoporosis. Rat studies showed the safety and efficacy of K2.8,9,10 Over the past decade, more than a dozen human clinical trials have shown the safety and efficacy of K2 to treat a variety of forms of osteoporosis. The protocol for K2 use is consistent throughout these studies: 15 mg K2 taken three times per day with fat-containing meals. Adequate dietary fat is essential for optimal K2 absorption.11. Many of the studies have focused on K2’s ability to reverse, or at least seriously slow down, post-menopausal osteoporosis. Due to the decrease in bone-friendly estrogen after menopause, osteoporosis with consequent fractures is common among women. One 24-month study compared K2 to the biphosphonate drug etidronate, with the control group getting only a calcium supplement. After two years, both the etidronate and K2 groups had significant increases in bone mineral density compared to the control group, with etidronate doing even better than the K2. Yet the incidence of new vertebral fractures was radically less in both the K2 and etidronate groups: 65 percent and 70 percent less than the control groups, respectively.12.Another study found that “a combination of risedronate and vitamin K2 has a synergistic effect on preventing the deterioration of trabecular bone architecture induced by estrogen deficiency. Some studies have shown that combined treatment with etidronate and vitamin K2 appears to be more effective than etidronate alone in the prevention of new osteoporotic vertebral fractures.”13 Other studies have found that the combination of vitamin D3 and K2 works better than D3 or K2 alone in increasing bone mineral density in postmenopausal osteoporotic women.14 Yet other studies have obtained excellent results in increasing bone mineral density/reducing fracture rates with just 45 mg K2 per day.15,16.
Menatetrenone (K2) and Bone Health
The Japanese have pioneered the use of K2 (menatetrenone, or MK4) supplements to treat osteoporosis. Rat studies showed the safety and efficacy of K2.8,9,10 Over the past decade, more than a dozen human clinical trials have shown the safety and efficacy of K2 to treat a variety of forms of osteoporosis. The protocol for K2 use is consistent throughout these studies: 15 mg K2 taken three times per day with fat-containing meals. Adequate dietary fat is essential for optimal K2 absorption K2 has been used clinically to treat other forms of osteoporosis with success as well. K2 has successfully prevented the bone loss that normally occurs in kidney dialysis patients.17,18 K2 stopped bone loss in liver cirrhosis patients.19 In an 11-month study of recovering anorexia patients, K2 cut bone loss 60 percent compared to the control group.20 In a 12-month study of 120 female Parkinson’s disease patients, the fracture incidence in the K2 group was only 10 percent of the control group’s fracture rate!21 K2 also increased bone mineral density and reduced the fracture rate in a 12-month study of 108 stroke patients with one-sided paralysis.22.K2: Multiple Effects
K2 has been shown to help build strong bones through multiple mechanisms. It protects osteoblasts, the cells that build new bone, from apoptosis (programmed cell death).23 K2 also causes many mature osteoclasts to undergo apoptosis, and inhibits the formation of new ones.24 Osteoclasts are the cells that destroy existing bone. While some are necessary, with aging and osteoporosis osteoclasts become more numerous, while osteoblasts become fewer in number. So bone destruction overwhelms bone building. K2 also inhibits the formation and bone-destroying activity of prostaglandin E2 (PGE2), an inflammatory eicosanoid intimately involved at the molecular level in promoting bone breakdown.25,26 Another study that showed K2 inhibited the bone-destroying activity of PGE2 also found that K1 had no PGE2-inhibiting activity.27 K2 also preserves the microstructure of trabecular bone, the spongy bone found at the ends of long bones, which tends to disintegrate with age or osteoporosis.28,29 K2 also opposes the bone-destroying effects of glucocorticoids (cortisol, prednisone).30,31.K2 and Cancer
In 1994 it was reported that K2, but not K1, could promote the differentiation of various types of leukemia cells. “Leukemia” is a broad, general term used to describe various malignant blood cell diseases which involve abnormally large numbers of immature white cells and damaged bone marrow. If not successfully treated, leukemia is usually eventually fatal. Toxic chemotherapy drugs are often used to treat it. By causing the leukemia cells to differentiate, K2 helps the cells to transform into more normal, nonleukemic cells. According to the study, “[Vitamin] K2 may be safely used in differentiation therapy [of leukemia] in combination with other inducers.”32 In 1997, another research group reported that K2 “showed a potent apoptosis-inducing activity for all freshly isolated leukemia cells tested” but that K1 had no anti-leukemia activity.33.By 2001, a Japanese research group had found that K2 had a dual effect, depending on the unique genetic makeup of the various leukemia cells tested. K2 killed some leukemia cells by apoptosis, and those that were genetically resistant to K2’s apoptotic activity were stimulated to differentiate instead. Miyazawa and colleagues concluded: “The dichotomous nature of [vitamin] K2 against leukemia cells appears to have clinical benefits for the treatment of patients with leukemias and myelodysplastic syndromes.”34
In 2003, the Miyazawa group published a study showing that K2 could kill (by apoptosis) a variety of different types of lung cancer cells, including small cell carcinomas, adenocarcinomas, squamous cell carcinomas and large-cell carcinomas. “Since [vitamin] K2 is a safe medicine without prominent adverse effects…our data strongly suggest the therapeutic possibility of using [vitamin] K2 for the treatment of patients with lung carcinoma.”35
In 2004 another Japanese research group found that K2 inhibits the growth and invasion of hepatocellular carcinoma (liver cancer) cells both in vitro and in vivo. Giving K2 to “mice inoculated with liver tumor cells reduced both tumor growth and body weight loss.”36 In July, 2004, the first human clinical trial results were announced in JAMA (The Journal of the American Medical Association). Forty women diagnosed with viral liver cirrhosis between 1996 and 1998 were randomly assigned either to a group receiving 45 mg K2 daily or the control group. By the end of the study, two of 21 women given K2 had developed liver cancer, while nine of 19 control group women had developed liver cancer. The results were found to be statistically significant, and a role for K2 in preventing liver cancer was proven.37
K2: You’re Arteries’ Best Friend?
Animal studies have shown that K2, but not K1, can inhibit the calcification of arterial plaque. As a recent review notes: “Calcification of the vessel walls is one of the features of atherosclerosis and is by itself considered to be a risk factor for plaque rupture.”38 And plaque rupture in a heart artery is often the final trigger for a (possibly fatal) myocardial infarction (heart attack). A 1996 study found that high-dose K2 inhibited the increase in aortic or kidney calcium induced by megadose synthetic vitamin D2. The authors noted that “a pharmacological dose of vitamin K2 might have a usefulness for the prevention and treatment of arteriosclerosis with calcification.”39 A 1999 study found that high-dose K2 could inhibit the increase in aortic calcium in rats made arteriosclerotic by high-dose D2 and an atherogenic diet.40A 1997 rabbit study found that high dose K2 “prevents both the progression of atherosclerosis and the coagulative tendency by reducing the total-cholesterol, lipid peroxidation and factor X activity in plasma, and the ester cholesterol deposition in the aorta of hypercholersterolemic rabbits.”41 In 2003 Spronk and colleagues reported “that MK-4 [K2] and not K1 inhibits warfarin-induced arterial calcification.”42
Most importantly, a study published in 2001 examined more than 4,000 humans followed from 1990 to 1996. Subjects were examined for their dietary K2 intake. Those with a “high” K2 intake (greater than 33 mcg per day) had only 43 percent of the risk of suffering a heart attack compared to the low K2 group (less than 22 mcg per day). The risk of dying from a heart attack was only 37 percent as high in the high-K2 group compared to the low-K2 group. “The dietary intake of vitamin K1 showed no consistent relation with cardiac events or aortic atherosclerosis.”43
K2: Anti-Aromatase?
One intriguing study on male rats suggests that K2 might be useful in suppressing the excess estrogen all too common in aging men. When aging male rats were fed a calcium-deficient diet, their serum estradiol levels rose 430 percent. K2 significantly reduced the elevated estrogen levels. The estrone level in serum of the K2-fed rats fell to a level lower than the control rats fed a regular calcium diet. The study’s authors suggest that K2 suppressed testicular aromatase in calcium deficient rats, reducing estrogen production, and that the increased estrogen production in the calcium-deficient rats not given K2 might be a compensating mechanism to prevent osteoporosis.44 This in turn suggests that the frequent elevation of estrogen seen in aging men might be the body’s way of preventing osteoporosis, which is more common in women than men. Taking high-dose K2 just might suppress male aromatase activity, suppressing male estrogen overproduction, yet still prevent osteoporosis.Megadose K2: Safety
The high dose of 45 mg K2 daily has been used in dozens of human studies, many lasting one to two years. Many of these studies emphasize the safety of K2. “Administration of menatetrenone [MK4/K2] was well tolerated. Given the absence of toxicity, menatetrenone can be recommended for all patients with MDS-RA.”45 “The adverse events were 2 cases of mild skin rash [out of 43 patients] which subsided after cessation of medication.”16 “menatetrenone can be used safely for [at least] 1 year in CAPD patients.”17 “No adverse effects of vitamin K2 were noted.”19 “No adverse effect was observed.”30 One concern some people might have with high-dose K2 is that it might cause “overcoagulation” of the blood. The 1997 rabbit study previously mentioned specifically noted that “The excessive dose of vitamin K2…did not promote the coagulative tendency in the rabbits.”41A 2001 study very carefully examined a range of variables that might indicate excessive blood-clotting tendency due to high-dose K2 in 29 elderly patients. The authors noted: “No changes in the sensitive molecular markers such as TAT and F1+2, which reflect the amount of thrombin [a pro-clotting substance] generated in the bloodstream, were observed…These results indicate that MK4 [K2] can be administered safely, with regard to maintaining the hemostatic balance [normal blood clotting], to osteoporotic patients receiving no anticoagulant therapy.”46
The one caution in using high-dose K2 is the use of warfarin (Coumadin®) anticoagulant therapy. Anyone taking warfarin or other similar “blood-thinning” drugs must NOT use high-dose K2. Indeed, such patients are usually counseled to avoid even high K1-containing foods, such as green vegetables, since warfarin works by opposing vitamin K’s blood coagulation effects. Menatetrenone, a Vitamin K2 Analogue, Inhibits Hepatocellular Carcinoma Cell Growth by Suppressing Cyclin D1 Expression through Inhibition of Nuclear Factor B Activation
Iwata Ozaki1,2, Hao Zhang1,3, Toshihiko Mizuta1, Yasushi Ide1, Yuichiro Eguchi1, Tsutomu Yasutake1, Toshiyuki Sakamaki4, Richard G. Pestell4 and Kyosuke Yamamoto1
Authors’ Affiliations: 1 Division of Hepatology and Metabolism, Department of Internal Medicine, and 2 Health Administration Center, Saga Medical School, Saga University, Nabeshima, Saga, Japan; 3 Second Department of Surgery, China Medical University, Heping District, Shenyang, China; and 4 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, District of Columbia
Requests for reprints: Iwata Ozaki, Health Administration Center, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan. Phone: 81-952-34-3215; Fax: 81-952-34-2017;
Purpose
Menatetrenone, a vitamin K2 analogue, plays an important role in the production of blood coagulation factors. Menatetrenone has also bee shown to have antineoplastic effects against several cancer cell lines including hepatocellular carcinoma (HCC) cells. However, the mechanisms by which vitamin K2 inhibits HCC cell growth have not bee fully clarified, and we therefore investigated the molecular basis of vitamin K2–induced growth inhibition of HCC cells.Experimental Design
HCC cells were treated with vitamin K2 and the expression of several growth-related genes including cyclin-dependent kinase inhibitors and cyclin D1 was examined at the mRNA and protein levels. A reporter gene assay of the cyclin D1 promoter was done under vitamin K2 treatment. The regulation of nuclear factor B (NF- B) activation was investigated by a NF- B reporter gene assay, an electrophoretic mobility shift assay, a Western blot for phosphorylated I B, and an in vitro kinase assay for I B kinase (IKK). We also examined the effect of vitamin K2 on the growth of HCC cells transfected with p65 or cyclin D1.Results
Vitamin K2 inhibited cyclin D1 mRNA and protein expression in a dose-dependent manner in the HCC cells. Vitamin K2 also suppressed the NF- B binding site-dependent cyclin D1 promoter activity and suppressed the basal, 12-O-tetradecanoylphorbol-13-acetate (TPA)–, TNF- –, and interleukin (IL)-1–induced activation of NF- B binding and transactivation. Concomitant with the suppression of NF- B activation, vitamin K2 also inhibited the phosphorylation and degradation of I B and suppressed IKK kinase activity. Moreover, HCC cells overexpressing cyclin D1 and p65 became resistant to vitamin K2 treatment.Conclusion
Vitamin K2 inhibits the growth of HCC cells via suppression of cyclin D1 expression through the IKK/I B/NF- B pathway and might therefore be useful for treatment of HCC.Vitamin K2 may curb liver cancer in women with viral cirrhosis Reuters Health Last Modified: November 1, 2001 Last Updated: 2004-07-21 10:42:10 -0400 (Reuters Health)
NEW YORK (Reuters Health) – Daily vitamin K2 supplementation may help prevent the development of hepatocellular carcinoma in women with viral cirrhosis of the liver, Japanese researchers report in the July 21st issue of the Journal of the American Medical Association.
Dr. Susumu Shiomi and colleagues from Osaka City University previously reported that daily vitamin K2 prevented bone loss in women with cirrhosis of the liver. (See Reuters Health report May 27, 2002). “The women in this original trial also satisfied criteria required for examination of the effects of vitamin K2 on the development of liver cancer,” Dr. Shiomi told Reuters Health.
In all, 40 women with viral liver cirrhosis who were admitted to the hospital between 1996 and 1998 were randomly assigned to 45 milligrams per day of vitamin K2 or to no vitamin K2. All women received dietary advice and symptomatic therapy for ascites as needed.
Liver cancer was detected in 2 of the 21 patients given vitamin K2 and 9 of the 19 controls. Thus, Dr. Shiomi reported that “the cumulative proportion of patients with liver cancer was smaller in the treated group.” After adjusting for factors including age, alanine aminotransferase activity, serum albumin, and total bilirubin, the risk ratio for the development of liver cancer in vitamin K2-treated women was 0.13.
“Despite its small size,” the authors note, “our study indicates that vitamin K2 decreases the risk of hepatocellular carcinoma to about 20% compared with the control group, suggesting that vitamin K2 may delay the onset of hepatocarcinogenesis.” JAMA 2004;292:358-361.
Vitamin K2-induced antitumor effects via cell-cycle arrest and apoptosis in gastric cancer cell lines. Third Department of Surgery and First Department of Internal Medicine, Tokyo Medical University, Tokyo, Japan.Vitamin K2 (VK2) has a growth inhibitory effect on various types of cancer cells in vitro, and its efficacy has been demonstrated in clinical applications in a number of patients with leukemia and hepatocellular carcinoma. In this study, the effect of cell growth inhibition and apoptosis induction and the concomitant use of an anticancer agent by VK2 (menaquinone: MK4), on gastric cancer cell lines were examined. When 4 kinds of gastric cancer cells (KATO III, MKN7, MKN74 and FU97) were exposed to MK4, the cell growth was inhibited in an MK4 dose-dependent manner. Morphologically, apoptosis induced by MK4 was recognized in FU97, but only a slight number of apoptotic images was recognized in other cell lines. On the contrary, in all the cell lines, the percentage of APO2.7 positive cells increased significantly in the MK4-treated group as compared to the controls. Caspase-3 activity increased significantly in KATO III and FU97 as compared to the controls, while no significant differences were noted in MKN7 or MKN74. Moreover, in all the cell lines, the percentage of G0/G1-phase cells ( approximately 70% in KATO III and FU97, and > or =80% in MKN7 and MKN74) increased in comparison to the controls, suggesting that cell-cycle arrest had occurred. All of the gastric cancer cell lines were given MK4 in different concentrations and two kinds of anticancer agent, with the result that cell growth was inhibited by the anticancer agent in a dose-dependent manner when it was given with MK4 in concentrations of up to 10 microM. In conclusion, our results demonstrate that the effect of MK4 on apoptosis and cell-cycle arrest differs in differentiated (MKN7, MKN74) and undifferentiated (KATO III, FU97) gastric cancer cell lines, and that MK4 alone or with anticancer agents has an antitumor effect on gastric cancer cell lines.
Int J Oncol. 2005; 26(1):33-40 Yokoyama T; Miyazawa K; Yoshida T; Ohyashiki K First Department of Internal Medicine, Tokyo Medical University, Nishishinjuku, Shinjuku-ku, Tokyo, Japan
Imatinib mesylate, an inhibitor of tyrosine kinases including BCR-ABL and KIT, inhibits the growth inhibition of small cell lung cancer (SCLC) cell lines in vitro. However, clinical trials of imatinib mesylate alone in patients with SCLC resulted in unsatisfactory outcomes. Vitamin K2 (menaquinone-4: VK2) induces apoptosis and differentiation in leukemia cells. We recently reported that VK2 also induces apoptosis in lung cancer cell lines. In the present study, we focused on the in vitro combined effects of imatinib mesylate plus VK2 on SCLC cell lines such as LU-139, LU-130, NCI-H69 and NCI-H128. Treatment with imatinib mesylate and VK2 for 96 h resulted in suppression of cell growth in a dose-dependent manner in all cell lines tested. The 50% inhibitory concentration (IC50) for imatinib mesylate ranged from 17-29 microM, whereas the IC50 for VK2 ranged from 16-64 microM. Combined treatment of imatinib mesylate plus VK2 resulted in pronounced inhibition of cell growth. The morphologic features of cells treated with imatinib mesylate and VK2 were typical of apoptosis. Since VK2 is a safe medicine without prominent adverse effects, treatment of patients with SCLC could derive therapeutic benefits from a combination of imatinib mesylate and VK2.
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