Inhibitory Effects of Isoflavones on Tumor Growth and Cachexia in Newly Established Cachectic Mouse Models Carrying Human Stomach Cancers

Abstract

Cachexia, a negative prognostic factor, worsens a patient's quality of life. We established 2 novel cachexia models with the human stomach cancer cell line MKN-45, which was subcloned to produce potent cachexia-inducing cells by repeating the xenografts in immune-deficient mice. After subsequent xenografts, we isolated potent cachexia-inducing cells (MKN45cl85 and 85As2mLuc). Xenografts of MKN45cl85 cells in mice led to substantial weight loss and reduced adipose tissue and musculature volumes, whereas xenografts of 85As2mLuc cells resulted in highly metastatic and cachectic mice. Surgical removal of tumor tissues helped the mice regain body-weight in both mouse models. In vitro studies using these cells showed that isoflavones reduced their proliferation, implying that the isoflavones possess antiproliferative effects of these cancer cell lines. Isoflavone treatment on the models induced tumor cytostasis, attenuation of cachexia, and prolonged survival whereas discontinuation of the treatment resulted in progressive tumor growth and weight loss. The inhibitory effects of tumor growth and weight loss by isoflavones were graded as soy isoflavone aglycone AglyMax > daidzein > genistein. These results demonstrated that the 2 novel cachectic mouse models appear useful for analyzing the mechanism of cancer cachexia and monitoring the efficacy of anticachectic agents.

ACKNOWLEDGMENTS

This work was supported by a Grant-in-Aid for the Third-Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare, Japan; a Grant-in-Aid for Scientific Research (C) from Ministry of Education, Culture, Sports, Science and Technology, Japan; the National Cancer Center Research and Development Fund (23-A-2); and the Foundation for Promotion of Cancer Research in Japan. We are grateful to Professor Emeritus Dr. A. Ito (Hiroshima University, Hiroshima, Japan) and Dr. M. Takebe (Nichimo Co., Ltd., Tokyo, Japan) for helpful discussions and providing the generous gift. We thank Professor Emeritus Dr. T. Suzuki (Fukushima Medical University, Fukushima, Japan) for the supply of 3 stomach cancer cell lines. We also thank R. Nakanishi, T. Komatsu, and K. Otsubo for their excellent technical assistance.

Nichimo Co., Ltd. holds the intellectual property of the soy isoflavone aglycone AglyMax product. All other authors have no conflicts of interest that would prejudice the impartiality of this scientific work.