The small molecule STF-62247 induces apoptotic and autophagic cell death in leukemic cells
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Tomohiro Kozako1,*, Keisuke Sato1,2,*, Yuichiro Uchida3, Naho Kato1, Akiyoshi Aikawa1, Kentaro Ogata2,4, Hidetoshi Kamimura2,4, Haruna Uemura2, Makoto Yoshimitsu3,5, Kenji Ishitsuka3,5, Yasuki Higaki6, Hiroaki Tanaka6, Shin-Ichiro Honda1 and Shinji Soeda1
1Department of Biochemistry, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan
2Department of Pharmacy, Fukuoka University Hospital, Fukuoka, Japan
3Division of Hematology and Immunology, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
4Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan
5Department of Hematology and Immunology, Kagoshima University Hospital, Kagoshima, Japan
6Faculty of Sports and Health Science, Fukuoka University, Fukuoka, Japan
*These authors have contributed equally to this work
Tomohiro Kozako, email: [email protected]
Keywords: Human T cell leukemia virus-1; adult T cell leukemia/lymphoma; apoptosis; autophagy; STF-62247
Received: July 20, 2017 Accepted: April 05, 2018 Published: June 12, 2018
Adult T cell leukemia/lymphoma (ATL) is an aggressive malignant T cell disease caused by human T cell leukemia virus-I (HTLV-1). Treatment outcomes for aggressive subtypes of ATL remain poor, with little improvement in overall survival since HTLV-1 was discovered. Therefore, new therapeutic strategies for ATL are required. STF-62247 induces autophagy and selectively kills renal cell carcinoma without apoptotic cell death. Here, we demonstrate that STF-62247 reduced cell viability and resulted in autophagosome accumulation and autophagy in leukemic cell lines (S1T, MT-2, and Jurkat). Interestingly, STF-62247 induced apoptosis in HTLV-1-infected cell lines (S1T and MT-2), as indicated by DNA fragmentation and caspase activation, but not in non-HTLV-1-infected Jurkat cells; a caspase inhibitor did not prevent this caspase-associated cell death. STF-62247 also increased nuclear endonuclease G levels. Furthermore, STF-62247 reduced cell viability and increased the number of apoptotic cells in peripheral blood mononuclear cells collected from patients with acute ATL, which has a poor prognosis. Therefore, STF-62247 may have novel therapeutic potential for ATL. This is the first evidence to demonstrate the cell growth-inhibitory effect of an autophagy inducer by caspase-dependent apoptosis and caspase-independent cell death via autophagy and endonuclease G in leukemic cells.
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