• Open Access

Dual antitumor mechanisms of Notch signaling inhibitor in a T-cell acute lymphoblastic leukemia xenograft model

Authors

  • Shigeo Masuda,

    1. Department of Cell Therapy and Transplantation Medicine, University of Tokyo Hospital, Tokyo
    2. Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo
    3. Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi
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  • Keiki Kumano,

    1. Department of Cell Therapy and Transplantation Medicine, University of Tokyo Hospital, Tokyo
    2. Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo
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  • Takahiro Suzuki,

    1. Department of Cell Therapy and Transplantation Medicine, University of Tokyo Hospital, Tokyo
    2. Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo
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  • Taisuke Tomita,

    1. Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo
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  • Takeshi Iwatsubo,

    1. Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo
    2. Department of Neuropathology, Graduate School of Medicine, University of Tokyo, Tokyo
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  • Hideaki Natsugari,

    1. Department of Rational Medicinal Science, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo
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  • Arinobu Tojo,

    1. Department of Hematology and Oncology, Institute of Medical Sciences, University of Tokyo, Tokyo
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  • Makoto Shibutani,

    1. Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Tokyo
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  • Kunitoshi Mitsumori,

    1. Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Tokyo
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  • Yutaka Hanazono,

    1. Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi
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  • Seishi Ogawa,

    1. Department of Cell Therapy and Transplantation Medicine, University of Tokyo Hospital, Tokyo
    2. 21th Century COE Program, Graduate School of Medicine, University of Tokyo, Tokyo
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  • Mineo Kurokawa,

    1. Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo
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  • Shigeru Chiba

    Corresponding author
    1. Department of Cell Therapy and Transplantation Medicine, University of Tokyo Hospital, Tokyo
    2. Department of Clinical and Experimental Hematology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan
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To whom correspondence should be addressed. E-mail: schiba-tky@umin.net

Abstract

Constitutive activation of Notch signaling is required for the proliferation of a subgroup of human T-cell acute lymphoblastic leukemias (T-ALL). Previous in vitro studies have demonstrated the therapeutic potential of Notch signaling inhibitors for treating T-ALL. To further examine this possibility, we applied a γ-secretase inhibitor (GSI) to T-ALL xenograft models. Treatment of established subcutaneous tumors with GSI resulted in partial or complete regression of tumors arising from four T-ALL cell lines that were also sensitive to GSI in vitro. To elucidate the mechanism of action, we transduced DND-41 cells with the active form of Notch1 (aN1), which conferred resistance to in vitro GSI treatment. Nevertheless, in vivo treatment with GSI induced a partial but significant regression of subcutaneous tumors that developed from aN1-transduced DND-41 cells, whereas it induced complete regression of tumors that developed from mock-transduced DND-41 cells. These findings indicate that the remarkable efficacy of GSI might be attributable to dual mechanisms, directly via apoptosis of DND-41 cells through the inhibition of cell-autonomous Notch signaling, and indirectly via disturbance of tumor angiogenesis through the inhibition of non-cell-autonomous Notch signaling. (Cancer Sci 2009; 100: 2444–2450)

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