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A scientific review of the oncogenic effects rice bran arabinoxylan compound (RBAC).

Introduction

Rice bran arabinoxylan compound (RBAC) is derived from the principal constituent of the hemicellulose B found in rice bran known as arabinoxylan, which is composed of arabi nose and xylose. It is then hydrolyzed by a beneficial carbohydrase enzyme complex obtained from shiitake mushroom mycelia culture. The result of this process is the creation of a health-promoting product with profound immunological effects.

RBAC has undergone an extensive toxicity study demonstrating that it is completely safe. The LD50 (lethal dose, 50%) of RBAC is greater than 36.0 g/ kg and is thus considered nontoxic; the Ames test for mutagenicity was negative. More sophisticated toxicity testing, including subchronic toxicity study (90-day dietary study in rats), guinea pig antigenicity study, and genotoxic testing, all demonstrate that RBAC is completely nontoxic. (1),(2) It is available as "BioBran" in Europe. It was previously sold as MGN-3 in the US and is now available as BRM4. Numerous human, animal, and cell-culture studies have been performed using RBAC, demonstrating its immunomodulating effects in immunocompromised states due to cancer.

A Summary of Animal and Cell Line Studies

Studies have shown that RBAC can reduce the toxicity of several chemotherapeutic agents, while at the same time sensitizing cancer cells to the therapeutic effect of the agent. (3) Eight groups of 10 Sprague-Dawley rats were randomly assigned to a group to receive water, cisplatin, or doxorubicin as a single dose on day 3, along with RBAC (MGN-3) at a dose of 5 mg/kg and 50 mg/kg for 11 days. All rats receiving the RBAC with chemotherapy at both doses showed a significant increase in body weight (approximately 72%), while the groups receiving chemotherapy without RBAC showed a significantly smaller increase in body weight (-1.5% for cisplatin, +30% for doxorubicin). Comparing the two doses of RBAC along with chemotherapy, the 5 mg/ kg group produced a +11% increase in weight gain in rats receiving cisplatin and a +46% weight gain in rats receiving doxorubicin, while the 50 mg/kg groups experienced a + 43% weight gain with cisplatin and a 43% increase in doxorubicin-treated rats. The chemotherapeutic agents caused diarrhea in treated rats. RBAC reduced the incidence of diarrhea to 50% and 40% at the 5 mg/kg and 50 mg/kg doses, respectively. Gross gastrointestinal mucosal pathology was observed in 70% of rats from the administration of cisplatin, which was decreased to 40% after 5 mg/kg and 50% after 50 mg/kg administration of RBAC. Doxorubicin produced diarrhea in 20% of the rats, which was reduced to 0% after the 5 mg/kg dose and to 10% after 50 mg/kg of RBAC. Gross intestinal pathology occurred in 50% of rats after administration of doxorubicin, and the incidence was decreased to 10% after 5 mg/ kg and to 30% after

50 mg/kg after administration of RBAC.

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It is unknown why, for some of the chemotherapeutic toxicity, the lower dose of RBAC appeared to be more effective. There was also a significantly decreased mortality due to cisplatin in both groups of rats receiving both doses of RBAC. Both cisplatin and doxorubicin administration are associated with the same pathology as found in the rats as well as severe cardiac and renal pathology in humans. This study used lower doses of the chemotherapeutic agents that could cause significant pathologic changes in the heart, liver, and kidneys. RBAC has previously been shown in both humans and animals to increase natural killer (NK) cell activity (especially in immunocompromised patients), tumor necrosis factor alpha and interferon-alpha from peripheral blood lymphocytes, and augmentation of NK cell cytotoxic function.

This study demonstrates that RBAC appears to be effective in protection against some of the disturbing side effects of chemotherapy, may be valuable in improving quality of life in patients receiving treatment, and may be a useful adjuvant to cancer chemotherapy. (3) Another study examining the effects of RBAC on weight loss and major and acute adverse effects of cisplatin found similar results and confirmed that the immunoreactive substances from RBAC are absorbed and protected against the adverse effects of the chemotherapeutic agent. (4)

The effect of RBAC was investigated on death receptor-induced apoptosis in the human leukemic HUT 78 cell line. HUT 78 cells were pretreated with RBAC and then incubated with the agonistic antibody against death receptor (Fas, CD95). In a dose-dependent manner, RBAC enhanced anti-CD95 antibody-induced apoptosis. Increased cell death was correlated with increased depolarization of mitochondrial membrane potential and increased activation of caspase 3, caspase 8, and caspase 9. RBAC treatment had no effect on the level of CD95, but it caused downregulation of Bcl-2 expression. These results suggest that RBACincreases the susceptibility of cancer cells to undergo apoptosis mediated by death ligands. (5)

The chemo-sensitizing effect of RBAC against human breast cancer cells was investigated in another study. MCF-7 and HCC70 cells were cultured with different concentrations of daunorubicin in the presence or absence of selected concentrations of RBAC (100-1000 [mu]g/ml) for 3 days. Treatment with RBAC increased susceptibility of breast cancer cells to daunorubicin 5.5-fold for MCF-7 and 2.5-fold for HCC70 cells. The data demonstrate that RBAC is an effective chemo-sensitizer and may represent a novel adjuvant for the treatment of breast cancer. (6)

Swiss albino mice inoculated with Ehrlich ascites carcinoma were treated intraperitoneally on day 8 after inoculation with RBAC and compared to controls. RBAC caused a significant delay in both tumor volume (63.27%) and tumor weight (45.2%), while inducing a 1.8-fold increase in the percentage of apoptotic solid Ehrlich carcinoma cells. RBAC also influenced plasma cytokine production by increasing levels of tumor necrosis factor-alpha and interferon-gamma (both known to have strong antitumor activity) while downregulating levels of the immunosuppressing cytokine interleukin-10. RBAC has been shown in this and numerous animal studies to increase NK cells that also play an important role in immune surveillance against cancer. (7)

A similar study conducted with murine solid Ehrlich carcinoma also demonstrated that RBAC significantly suppressed the growth of tumors and found that the suppression is associated with normalization of the lipid peroxidation (LPx) and augmentation of glutathione (GSH) contents. RBAC enhanced the activity of the endogenous antioxidant-scavenging enzymes superoxide dismutase (SOD); glutathione peroxidase (GPx); catalase (CAT); and glutathione-S-transferase (GST) in blood, liver, and tumor tissue. Similarly, it upregulated the expression of GPx, SOD1, and CAT mRNA in the liver. The effect of RBAC was more pronounced when animals were treated early at day 4 of tumor cell inoculation, as compared with later treatment at 11 days. RBAC induced oncostatic activity by modulating lipid peroxidation, augmenting the antioxidant defense system and protecting against oxidative stress. In addition to its immunomodulating activity, RBAC appears to have a radical-scavenging effect in vivo after exposure to cancer cells. (8)

A Summary of Human Studies

A long-term study (24 months) was conducted with 16 cancer patients who had just completed surgery, radiation therapy, and/or chemotherapy. Patients received 3 grams of RBAC per day. Two patients were diagnosed with stomach cancer, 3 patients with large intestine cancer, 3 with breast cancer, 3 with rectal cancer, 1 with biliary tract cancer at the hepatic portal, 1 with ovarian cancer, 1 with thyroid cancer, 1 with lung cancer, and 1 with uterine/cervical cancer. Body weight increased in 10 patients, decreased in 2, and was unchanged in 4. The leukocyte count was generally low in the patients and below the normal range in 7 of 16 patients (44%). After 6 months of RBAC, the leukocyte count increased in 9 of 16 patients, and 3 of them achieved a normal value. One patient had a very low leukocyte count completely normalize, and another had a very high leukocyte count normalize. The NK cell activity at baseline was > 30% in 11 patients, 30% to 50% in 3 patients, and [greater than or equal to] 50% in 2 patients. Only 19% of patients had normal NK cell activity. After administration of RBAC, NK activity increased and the level normalized in 11 (69%) patients. Tumor markers decreased in 10 (63%) patients after administration of RBAC. No adverse reaction was reported. (9)

A 64-year-old man diagnosed with terminal pancreatic cancer with metastases and ascites, who was not a candidate for radical surgery, received chemotherapy, was unable to tolerate the side effects, and did not appear to receive any therapeutic effect. He opted for oral outpatient treatment that included Furtulon 1,200 mg and Endoxan 200 mg. His tumor markers rose rapidly (CEA 460.0 ng/mL, CA 19-9 54,000 U/mL), and anorexia and pain increased despite the outpatient treatment. The patient requested RBAC and started taking 3 grams per day on January 7, 2000, approximately two months after taking the oral chemotherapy. One month after taking RBAC, the tumor markers remained stable and stopped increasing, the ascites and anorexia improved, and body weight improved as well. Three months after taking RBAC, tumor markers rapidly decreased (CEA 93.6 ng/mL, CA 19-9 6,300 U/mL); and leukocyte, lymphocyte, granulocyte, and monocyte counts improved as well. CT images showed a marked reduction in the pancreatic tumor and liver metastases after 5 months of treatment with RBAC. By May 13, 2000, the diameter of the pancreatic lesion was almost nonmeasurable, and the liver metastases significantly reduced. On December 20, 2000, a CT scan revealed that there was almost no abnormality seen in the pancreas or liver, and a stomach lesion previously seen on the anterior wall completely disappeared. A biopsy of the stomach revealed no malignant tumor cells. The patient had been told that he had 3 months to live after his initial diagnosis and conventional treatment; the chemotherapy was only for palliative care. He lived for 17 months and later died in the hospital from hematemesis. The cause of the hematemesis was unknown and was found to be unrelated to the cancer. His tumor markers were normal just before his death. (10)

Another case is a 64-year-old female with umbilical metastasis of recurrent cancer (Sister Mary Joseph's nodule, SMJN) who survived for several years after diagnosis, using an integrative approach with chemotherapy and 3 grams per day of RBAC. SNJN is a very rare cancer with a mean survival time of 4.9 months after diagnosis. The patient underwent a resection of the ascending colon in April 2000; was diagnosed with a recurrence (SNJN) in January 2001; and was told that an operation was not possible and that she would only live several months, even with conventional treatment. She refused chemotherapy and agreed only to take RBAC. Her NK cell activity increased in a few months from 41% to 55%, but over the course of time her CEA increased and the tumor continued to grow. In July 2003 she received chemotherapy, 5-FU 500 mg, Isovorin 250 mg, and 10A plus Topotecin 40 mg once per week and was able to tolerate the drug therapy. In December 2003 she asked to stop the chemotherapy, since the tumor had started to grow again after a few months of drug treatment. She was still alive on February 17,2004.(11)

A quality of life (QOL) study was conducted with 205 progressive and partially metastasized cancer patients in late (III-IV) stages after surgery. All patients were treated with complementary therapy that included medications with fewer known side effects, Gerson's diet therapy, vitamins, pro- and prebiotics, thermotherapy (far infrared with locust leaves), superoxide dismutase, coffee enemas, Oriental medicines, and germanium. The patients were hospitalized for 6 months and randomly assigned to either the control group (n = 109) that received the treatment without RBAC or the group (n = 96) that received the same treatment with 3 grams of RBAC daily. Patients were followed for 18 months. NK cell activity and QOL were assessed in all patients at baseline. The NK cell activity was generally low at baseline. The rate of patients with unchanged or increased NK cell activity was higher in the group receiving RBAC compared with the control group, resulting in a 1.5 times higher survival rate in the integrative group compared to controls. The survival rate at 18 months was 54.2% for the RBAC group (52 patients) and 35.8% (19) in the control group. None of the dropouts from the control group survived. If dropouts were taken into account, the survival rate for the control group was 17.4% of the 109 patients. Appetite and QOL improved in the RBAC group compared with controls. There was a 49% dropout rate in the control group due to increased pain, malaise, vomiting, decreased appetite, and poor emotional outlook. The findings indicate that NK activity can be used as a pathological index of progressive cancer and may be improved with RBAC. Although both groups received the same extensive complementary program, it appears that receiving RBAC was responsible for the difference between them. (12)

The effect of RBAC on NK activity was studied in 32 cancer patients with different types of malignancies that included prostate, breast, plasma cell, and blood/bone marrow. The majority of the patients first went through debulking treatment with surgery, radiation, or chemotherapy. Tumor antigens and NK cell activity were measured prior to patients' taking RBAC and one month posttreatment. Initially, patients demonstrated a significantly low level of NK cell function. One month after taking RBAC, a significant increase in NK activity (up to 10-fold) was observed. The augmentation of NK cell activity was detected in all types of cancer. It appeared that as NK cell activity increased, tumor markers decreased. Individuals varied in response to the augmentation effects of RBAC. Their NK cells demonstrated an increase in the binding capacity and killing of cancer cells, as well as more granularity. The important role of granules in NK cells' destruction of their tumor targets has been shown by the observation that isolated and purified granules are lytic for a variety of tumor cells types. T- and B-cell proliferation was also shown to increase in patients after taking RBAC. This study demonstrates that RBAC causes overall immune stimulation. Patients were followed for 4 years while taking RBAC, with no recurrences noted for the duration of the study. The authors' previous research demonstrated that RBAC increases NK cell activity, other immune cells, and T- and B-cells in normal healthy subjects. (13)

Discussion

This review examines key studies that were published examining the effect of RBAC on malignancy. (3-13) It is important to note that, although RBAC is a dietary supplement, it was developed and researched using a drug model. This is significant, because there are a plethora of dietary supplements that claim to affect cancer in various ways with little or no scientific validation. It is imperative, especially for a potentially fatal disease such as cancer where conventional medicine has not made any true difference in overall survival for the last 40 years, to be able to select those dietary supplements with the greatest chance of having a positive impact on the disease and ultimately the patient.

RBAC enhances the activity of the endogenous antioxidant-scavenging enzymes. It induces oncostatic activity by modulating lipid peroxidation, augmenting the antioxidant defense system, and protecting against oxidative stress. In addition to its immunomodulating activity, RBAC appears to have a radical-scavenging effect in vivo after exposure to cancer cells. (8)

Studies have shown that RBAC is able to modulate the immune system in the direction that would most benefit a cancer patient. It has been shown to downregulate immune-suppressing cytokines and upregulate immune-enhancing cytokines. RBAC increases NK cell activity and T- and B-cell proliferation. It also increases the granularity of NK cells. Cytoplasmic granules may represent one of the most important mechanisms to kill cancer cells by the NK cell system. (5-13)

An interesting study was conducted with 11 individuals exposed to toxic chemicals in the workplace. They demonstrated immune dysfunction as evidenced by low NK cell activity and low lymphocyte blastogenic responses to T- and B-cell mitogens. After receiving RBAC for 4 months at a dose of 15 mg/kg, NK cell activity increased 4- and 7-fold at 2 and 4 months respectively. T- and B-cell functions increased 130% to 150% higher than baseline. (14) RBAC was also shown to similarly augment immune function in normal healthy subjects, and future research should examine the potential cancer-protective benefit of RBAC. (13)

RBAC has been shown to have potential therapeutic benefit with other diseases that involve immune dysfunction. It was shown to inhibit HIV-1 replication by inhibition of HIV-1 p24 antigen production in a dose-dependent manner. RBAC at concentrations of 12.5, 25, 50, and 100 [mu]g/ml showed 18.3%, 42.8%, 59%, and 75% reduction in p24 antigen, respectively. RBAC also inhibited syncytia formation, and the inhibition was maximized (75%) at a concentration of 100 [mu]/g/ml. (15) Since RBAC has been shown to be completely safe without any negative side effects or toxicity, a study should be conducted with HIV + patients. Although newer drug treatments have dramatically improved quality of life and life span in HIV + patients, there is still an issue with developing drug resistance and immune dysfunction. Therefore, a study that compares supplementation of RBAC to placebo in HIV + patients who are presently undergoing drug therapy may prove useful.

A randomized, double-blind, placebo-controlled trial examined the effect of RBAC in 34 patients (14 males and 20 females, aged 25 to 70 years old) with irritable bowel syndrome (IBS). The patients were allocated into either the RBAC (Group M) or placebo group (Group P), and given either 1 g of MGN-3 or placebo, twice daily for four weeks. The evaluation of symptoms revealed that, in Group M, stool frequency and feeling of incomplete evacuation tended to improve at 2 to 3 weeks after the start of treatment. Gastrointestinal Symptom Rating Scale (GSRS) scores for diarrhea and constipation also significantly declined. Furthermore, in the self-evaluation of effectiveness, more than 50% of the patients responded that the treatment was effective, selecting either "good" or "quite good" in the 5-point scale. In contrast, in Group P, no significant changes in GSRS scores were noted, and 25% of the patients responded that the treatment was effective in the self-evaluation. Hematologic tests revealed that both groups showed no remarkable changes in posttreatment white blood cell count or CRP levels, as compared with pretreatment levels. However, the rate of change in NK cell activity was significantly higher in Group M.

RBAC, with its anti-inflammatory and immunomodulating effects, was effective in some IBS patients. This study suggests that RBAC may be a potential treatment option for IBS in the future. (16) It would also be interesting to compare a 1 gram dose to a higher 3 gram dose in a future study of patients with IBS to see if a greater percentage of patients show improvement.

Summary

Animal and human research suggests that RBAC may sensitize cancer cells, making them more susceptible to chemotherapy; and it may have the potential to overcome drug resistance in cancer cells. Additionally, RBAC appears to protect normal healthy cells against the potentially damaging and toxic effects of chemotherapy. (3-6) Even more striking are the results of several human studies that demonstrate an oncostatic effect as evidenced by prolonged survival and in some cases remission with and without conventional treatment. (9-13) Case studies are presently being followed to further elucidate the oncostatic effects of RBAC and will be reported in the near future.

Notes

(1.) Daiwa Pharmaceutical Co. Ltd. BioBran rice bran arabinoxylan compound. http://www.daiwapharm.com/eng/product.html.

(2.) Tazawa K. BioBran/MGN-3: Basic and clinical application to integrative medicine. Japan: Iyakushuppan co. Publishers; 2003: 18-22.

(3.) Jacoby Jl, Wnorowski G, Sakata K, et al. The effect of MGN-3 on cisplatin and doxorubicin induced toxicity in the rat. Journal of Nutraceuticals, Functional & Medicinal Foods. 2001; 3(4):3-11.

(4.) Endo Y, Kambayashi H. Modified rice bran beneficial for weight loss of mice as a major and acute adverse effect of cisplatin. Pharmacol Toxicol. 2003;92:300-303.

(5.) Ghonenum M, Gollapudi S. Modified arabinoxylan rice bran (MGN-3/Biobran) sensitizes human T cell leukemia cells to death receptor (CD95)induced apoptosis. Cancer Lett. 2003;201:41-49.

(6.) Gollapudi S, Ghoneum M. MGN-3/Biobran, modified arabinoxlan from rice bran, sensitizes human breast cancer cells to chemotherapeutic agent, daunorubicin. Cancer Detect Prev. 2008;32:1-6.

(7.) El-Din B, Noaman E, Ghoneum M. In vivo tumor inhibitory effects of nutritional rice bran supplement MGN-3/Biobran on Ehrlich carcinoma bearing mice. Nutr Cancer. 2008;60(2):235-244.

(8.) Noaman E, Badr El-Din Nk, Bibars MA, et al. Antioxidant potential by arabinoxylan rice bran, MGN-3/Biobran, represents a mechanism for its oncostatic effect against murine solid Ehrlich carcinoma. Cancer Lett. 2008;268(2):348-59.

(9.) Tsunekawa H. Effect of long-term administration of immunomodulatory food on cancer patients completing conventional treatments. Clin Pharmacol Ther. 2004;14(3):295-302.

(10.) Kaketani, K. A case where an immunomodulatory food was effective in conservative therapy for progressive terminal pancreatic cancer. Clin Pharmacol Ther. 2004; 14(3):273-279.

(11.) Kawai T et al. One case of a patient with umbilical metastasis of recurrent cancer (Sister Mary Joseph's Nodule, SMJNI who has survived for a long time under immunomodulatory supplement therapy. Clin Pharmacol Ther. 2004;14(3): 281-288.

(12.) Takahara K, Sano K. The prolongation and QOL improvement effect of rice bran arabinoxylan derivative (MGN-3, BioBran) for progressive cancer. Clin Pharmacol Ther. 200;14(3):267-271.

(13.) Ghoneum M, Brown J. NK immunorestoration of cancer patients by MGN-3, a modified arabinoxylan rice bran (study of 32 patients followed for up to 4 years). In: Klatz RM, Goldman R, eds. Anti-Aging Medical Therapeutics. Vol. III. Health Quest Publications; 1998: 217-226.

(14.) Ghoneum M. Immunostimulation and cancer prevention. Presented at: The 7th International Congress on Anti-Aging & Biomedical Technologies. December 11-13, 1999. Tropicana Hotel, Las Vegas, NV.

(15.) Ghoneum M. Anti-HIV activity in vitro of MGN-3, an activate arabinoxylane from rice bran. Biochem Biophys Res Commun. 1998;243:25-29.

(16.) Kamiya T, Shikano M, Joh T. The Anti-Inflammatory and Immunomodulating Effects of Rice Bran Arabinoxylan Compound on Irritable Bowel Syndrome. 50th Annual Meeting of the Japanese Society of Gastroenterology. J Gastroenterol. 105, Special Issue.

by Shari Lieberman, PhD, CNS, FACN

Shari Lieberman, PhD, CNS, FACN drshari.net and drshari.com

Dr. Lieberman earned her PhD in Clinical Nutrition and Exercise Physiology from The Union Institute, Cincinnati, Ohio and her MS degree in Nutrition, Food Science, and Dietetics from New York University. She is a Certified Nutrition Specialist (CNS); a Fellow of the American College of Nutrition (FACN); a member of the American Academy of Anti-Aging Medicine (A4M); a former officer, present board member and chair of the exam committee for the Certification Board for Nutrition Specialists; and immediate past President of the American Association for Health Freedom. She is the recipient of the National Nutritional Foods Association 2003 Clinician of the Year Award and is in the Cambridge Who's Who Registry of Executives and Professionals. Her newest book--The Gluten Connection (Rodale 2007) and Transitions Glycemic Index Food Guide (Square 1 Publishers 2006) were just recently released. Dr. Lieberman's best-selling book The Real Vitamin & Mineral Book is now in its 4th Edition (Avery/Penguin Putnam, 2007). She is the author of The Mineral Miracle (Square 1 Publishers 2006), User's Guide To Brain-Boosting Supplements (Basic Health Publications, Inc., 2004), Dare To Lose: 4 Simple Steps to a Better Body (Avery/Penguin Putnam, 2003); Get Off the Menopause Roller Coaster (Avery/Penguin Putnam, 2002); Maitake Mushroom and D-fraction (Woodland Publishing, 2001; Maitake King of Mushrooms (Keats Publishing 1997) and All About Vitamin C (Avery Publishing Group, 1999). Dr. Lieberman is the Founding Dean of New York Chiropractic College's MS Degree in Clinical Nutrition; an industry consultant; a contributing editor to the American Medical Association's 5th Edition of Drug Evaluations; a peer reviewer for scientific publications; a published scientific researcher and a presenter at numerous scientific conferences. Dr. Lieberman is a frequent guest on television and radio and her name is often seen in magazines as an authority on nutrition. She has been in private practice as a clinical nutritionist for more than 20 years.

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Date:May 1, 2009
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