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Dynamic color-coded fluorescence imaging of the cell-cycle phase, mitosis, and apoptosis demonstrates how caffeine modulates cisplatinum efficacy

Authors

  • Shinji Miwa,

    1. AntiCancer, Inc., San Diego, California
    2. Department of Surgery, University of California, San Diego, San Diego, California
    3. Department of Orthopedic Surgery, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
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  • Shuya Yano,

    1. AntiCancer, Inc., San Diego, California
    2. Department of Surgery, University of California, San Diego, San Diego, California
    3. Division of Surgical Oncology, Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
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  • Yasunori Tome,

    1. AntiCancer, Inc., San Diego, California
    2. Department of Surgery, University of California, San Diego, San Diego, California
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  • Naotoshi Sugimoto,

    1. Department of Physiology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
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  • Yukihiko Hiroshima,

    1. AntiCancer, Inc., San Diego, California
    2. Department of Surgery, University of California, San Diego, San Diego, California
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  • Fuminari Uehara,

    1. AntiCancer, Inc., San Diego, California
    2. Department of Surgery, University of California, San Diego, San Diego, California
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  • Sumiyuki Mii,

    1. AntiCancer, Inc., San Diego, California
    2. Department of Surgery, University of California, San Diego, San Diego, California
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  • Hiroaki Kimura,

    1. Department of Orthopedic Surgery, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
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  • Katsuhiro Hayashi,

    1. Department of Orthopedic Surgery, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
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  • Elena V. Efimova,

    1. Ludwig Center for Metastasis Research, The University of Chicago, Chicago, Illinois
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  • Toshiyoshi Fujiwara,

    1. Division of Surgical Oncology, Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
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  • Hiroyuki Tsuchiya,

    1. Department of Orthopedic Surgery, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
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  • Robert M. Hoffman

    Corresponding author
    1. Department of Surgery, University of California, San Diego, San Diego, California
    • AntiCancer, Inc., San Diego, California
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  • Shinji Miwa and Shuya Yano contributed equally to this work.
  • None of the authors have a conflict of interest regarding this study.

Correspondence to: Robert M. Hoffman, Ph.D., AntiCancer, Inc., 7917 Ostrow Street, San Diego, CA 92111.

E-mail: all@anticancer.com

ABSTRACT

Caffeine enhances the effect of certain anticancer drugs, but the mechanism of modulation is poorly understood. In this study, modulation of cisplatinum efficacy induced by caffeine was visualized at the subcellular level by real-time fluorescent-protein imaging. Mitotic and apoptotic changes were observed by imaging 143B human osteosarcoma dual-color cells, in which GFP is expressed in the nucleus and RFP is expressed in the cytoplasm. Modulation of the cell cycle was imaged using time-lapse imaging of HeLa cells expressing a fluorescent ubiquitination-based cell cycle indicator (FUCCI) in the nucleus. Clonogenic assays showed that caffeine increased the inhibition by cisplatinum on cell proliferation. Subcellular imaging demonstrated that cisplatinum decreased mitosis and induced apoptosis in 143B cells. The combination of cisplatinum and caffeine enhanced mitosis and subsequently increased apoptosis. Time-lapse imaging showed that cisplatinum strongly induced cell-cycle arrest in the S/G2 phase in HeLa-FUCCI cells. Caffeine overcame the cell-cycle arrest induced by cisplatinum, thereby increasing its efficacy, since cisplatinum is ineffective against quiescent cells. The data in this report indicate that caffeine modulates the cell cycle in cancer cells, thereby enhancing efficacy of cell-cycle-dependent anticancer drugs such as cisplatinum. J. Cell. Biochem. 114: 2454–2460, 2013. © 2013 Wiley Periodicals, Inc.

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