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FF-10501 induces caspase-8-mediated apoptotic and endoplasmic reticulum stress-mediated necrotic cell death in hematological malignant cells

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Abstract

FF-10501 is a novel inhibitor of inosine monophosphate dehydrogenase (IMPDH). Clinical trials of FF-10501 for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are currently being conducted in the United States. Although it has been shown that FF-10501 induces apoptosis in hematological malignant cells, the intracellular mechanisms of this effect have not been characterized. We conducted an in vitro study to elucidate the mechanisms of FF-10501-induced cell death using 12 hematological malignant cell lines derived from myeloid and lymphoid malignancies. FF-10501 suppressed the growth of each cell line in a dose-dependent manner. However, the clinically relevant dose (40 μM) of FF-10501 induced cell death in three cell lines (MOLM-13, OCI-AML3, and MOLT-3). Investigation of the cell death mechanism suggested that FF-10501 induces both apoptotic and necrotic cell death. FF-10501-induced apoptosis was mediated by caspase-8 activation followed by activation of the mitochondrial pathway in MOLM-13 and MOLT-3 cells. FF-10501 induced necrotic cell death via endoplasmic reticulum stress in OCI-AML3 cells. The present study is the first to identify intracellular pathways involved in FF-10501-induced cell death.

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Acknowledgements

The authors would like to thank Miyuki Saisho, Eri Sakai-Nagamatsu, Misato Yagi, Mami Sato, Miku Kamekou, Ayaka Tsuzuki, Takafumi Kuroiwa, Midori Suekane, Kousuke Iwasaki, and Shuntarou Nakamura for their help with the experiments.

Funding

This research was partially supported by FUJIFILM Corporation.

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Authors and Affiliations

  1. Department of Drug Informatics, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1, Nanakuma, Jounan, Fukuoka, 814-0180, Japan

    Taichi Matsumoto, Keisuke Migita & Shuuji Hara

  2. Central Laboratory of Pathology and Morphology, Department of Medicine, Fukuoka University, Fukuoka, Japan

    Shiro Jimi

  3. Laboratory of Drug Design and Drug Delivery, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan

    Kazuki Terada

  4. Department of Pharmacotherapeutics, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan

    Masayoshi Mori

  5. Division of Medical Oncology, Hematology, and Infectious Diseases, Department of Medicine, Fukuoka University, Fukuoka, Japan

    Yasushi Takamatsu

  6. Department of Oncology/Hematology, Shimane University Hospital, Shimane, Japan

    Junji Suzumiya

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  1. Taichi Matsumoto
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Contributions

TM and SJ designed the research study. TM performed the experiments. TM, SJ, KT, and MM analyzed and interpreted the data. TM drafted the manuscript. SJ, KM, YT, JS, and SH revised the manuscript. SJ provided final approval of the current version for submission.

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Correspondence to Taichi Matsumoto.

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Matsumoto, T., Jimi, S., Migita, K. et al. FF-10501 induces caspase-8-mediated apoptotic and endoplasmic reticulum stress-mediated necrotic cell death in hematological malignant cells. Int J Hematol 110, 606–617 (2019). https://doi.org/10.1007/s12185-019-02722-x

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