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Synergistic Effects Induced by Cycloprodigiosin Hydrochloride and Epirubicin on Human Breast Cancer Cells

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Abstract

The effects of cPrG·HCl and epirubicin on the suppression of cell growth were examined on human breast cancer cell line (MDA-MB-231). Either cPrG·HCl or epirubicin alone showed a tumor growth inhibition in a time- and dose-dependent manner, however, the combinatory use of cPrG·HCl together with epirubicin resulted in prominent synergistic effects on the breast cancer cells. In the in vitro studies, the combinatory use of these two drugs accelerated apoptotic cell death as revealed by morphological changes as well as by the appearance of subG1 population by flow cytometry. In addition, confocal microscopy revealed that the accumulation of epirubicin in nucleus increased apparently when cPrG·HCl were present. In the in vivo assay, nude mice bearing xenografted tumor cells received 4 weeks of intraperitoneal administration of cPrG·HCl and epirubicin. After 12 days, the combinatory treatment significantly suppressed the tumor growth compared to the controls. The TUNEL staining revealed that tumor cells in cPrG·HCl plus epirubicin-treated mice exhibited a higher apoptotic rate. In addition, 31P-NMR studies on the xenografted tumor revealed that cPrG·HCl lowered tumor pHi (below pH 6.9), while it did not affected muscle pHi. No pathological changes were observed in any intrinsic organs and the serum alanine aminotransferase levels remained within normal limits among the groups. These results suggest that the combinatory use of cPrG·HCl and epirubicin may be useful for breast cancer therapy.

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Authors and Affiliations

  1. Departments of Surgery II, Kansai Medical University, Moriguchi, Osaka

    Daigo Yamamoto, Kanji Tanaka, Koji Nakai, Tetsuya Baden, Kentaro Inoue & Koshiro Hioki

  2. Departments of Medicine III, Kansai Medical University, Moriguchi, Osaka

    Chizuko Yamamoto & Hirota Takemoto

  3. Departments of Life Science, Faculty of Science, Himeji Institute of Technology, Kouto 3-2-1, Kamigori-cho, Ako-gun, Hyogo

    Keiko Kamato & Hajime Hirata

  4. Molecular Neurobiology Research Center, Shiga University of Medical Science, Seta, Ohtsu, Japan

    Shigehiro Morikawa & Toshiro Inubushi

Authors
  1. Daigo Yamamoto
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  2. Kanji Tanaka
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  12. Koshiro Hioki
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Yamamoto, D., Tanaka, K., Nakai, K. et al. Synergistic Effects Induced by Cycloprodigiosin Hydrochloride and Epirubicin on Human Breast Cancer Cells. Breast Cancer Res Treat 72, 1–10 (2002). https://doi.org/10.1023/A:1014940632674

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