MGN-3/Biobran, modified arabinoxylan from rice bran, sensitizes human breast cancer cells to chemotherapeutic agent, daunorubicin☆
Introduction
Chemotherapy is considered the cornerstone of treatment for many types of cancer. However, many chemotherapeutic agents exhibit dose-limiting toxicities including: congestive heart failure [1], myelosuppression [2], neutropenia, alopecia, mucositis, diarrhea, myalgias [3], [4], thrombocytopenia [5], neurotoxicity, immune-suppression, as well as mutagenic and carcinogenic effects [6], [7], [8], [9]. In addition, a majority of cancer patients treated with chemotherapy relapse and die from their disease. It is therefore of particular interest to explore therapeutic approaches that reduce chemotherapeutic-mediated toxicity. The use of chemotherapeutic agents in conjunction with safe, natural agents that act to incorporate them into less toxic, yet effective, combined-modality treatment may thus provide an answer to this urgent need.
MGN-3 is a natural product that is obtained by reacting rice bran hemicellulose with multiple carbohydrate hydrolyzing enzymes from Shiitake mushrooms. The main chemical structure of MGN-3 is arabinoxylan with a xylose in its main chain and an arabinose polymer in its side chain [10]. Previously, we presented evidence for the role of MGN-3 as a potent activator of human NK cells in healthy subjects [11], [12] and in cancer patients [13]. Recently, we have demonstrated that MGN-3 sensitizes human leukemic HUT 78 cells to anti-CD95 antibody-induced apoptosis [14]. In this study, we examined the sensitizing ability of MGN-3 toward the chemotherapeutic agent, daunorubicin (DNR) in human breast cancer cells (BCCs) and examined the possible mechanism underlying its effect.
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Tumor cell lines and culture conditions
Human breast cancer cell lines MCF-7 and HCC70 cells were used in the present study. Cells were purchased from American Tissue and Culture Collection (ATCC), Manassas, VA. Tumor cells were maintained in our laboratory in a complete medium (CM) that consisted of RPMI-1640, supplemented with 10% fetal calf serum (FCS), 2 mM glutamine, and 100 μg/ml streptomycin and penicillin.
Drugs and chemicals
DNR and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) were obtained from Sigma.
MGN-3
MGN-3 is a denatured
Effects of MGN-3 on the BCC survival
BCCs were co-cultured with MGN-3 (100–1000 μg/ml) for 3 days. Treatment of MCF-7 cells with MGN-3 resulted in a significant decrease in cell survival that followed dose-dependent fashion. Data in Fig. 1A shows the percentages of MCF-7 cell survival were 75, 70 and 63% post-treatment with MGN-3 at concentrations of 100, 500 and 1000 μg/ml, respectively. On the other hand, response of HCC70 cells to the apoptotic effect of MGN-3 was less remarkable (Fig. 1B).
Effects of MGN-3 on the sensitivity of BCCs to DNR
BCCs were cultured with DNR at different
Discussion
In this study, we examined the sensitizing effects of MGN-3 on human breast cancer cells to the chemotherapeutic agent, daunorubicin. Treatment with MGN-3 significantly increased susceptibility of MCF-7 and HCC70 cells to DNR 5.5- and 2.5-fold, respectively, as compared to cells treated with DNR alone. Earlier studies have shown a potential for MGN-3 in reducing chemo-toxic effects in murine and cancer patients. A beneficial effect of MGN-3 on some adverse actions of anticancer drugs was
Conflict of interest
None declared.
Acknowledgement
The authors would like to acknowledge Daiwa Pharmaceutical Co. Ltd., Tokyo, Japan, for the financial support of this project.
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Data was partially presented at The Int. Res. Conf. on Food, Nutrition and Cancer, Washington, DC, 15–16 July 2004.
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Both authors contributed equally to this work.