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SRT1720 induces SIRT1-independent cell death in adult T-cell leukemia/lymphoma.
Kozako, Tomohiro; Kato, Naho; Ohsugi, Takeo; Uchida, Yu-Ichiro; Yoshimitsu, Makoto; Ishitsuka, Kenji; Higaki, Yasuki; Sato, Haruna; Aikawa, Akiyoshi; Honda, Shin-Ichiro.
Afiliação
  • Kozako T; Department of Biochemistry, Faculty of Pharmaceutical Sciences, Fukuoka University, Japan.
  • Kato N; Department of Biochemistry, Faculty of Pharmaceutical Sciences, Fukuoka University, Japan.
  • Ohsugi T; Department of Laboratory Animal Science, School of Veterinary Medicine, Rakuno Gakuen University, Hokkaido, Japan.
  • Uchida YI; Division of Hematology and Immunology, Graduate School of Medical and Dental Sciences, Kagoshima University, Japan.
  • Yoshimitsu M; Division of Hematology and Immunology, Graduate School of Medical and Dental Sciences, Kagoshima University, Japan.
  • Ishitsuka K; Department of Hematology and Immunology, Kagoshima University Hospital, Japan.
  • Higaki Y; Division of Hematology and Immunology, Graduate School of Medical and Dental Sciences, Kagoshima University, Japan.
  • Sato H; Department of Hematology and Immunology, Kagoshima University Hospital, Japan.
  • Aikawa A; Faculty of Sports and Health Science, Fukuoka University, Japan.
  • Honda SI; Department of Biochemistry, Faculty of Pharmaceutical Sciences, Fukuoka University, Japan.
FEBS J ; 289(12): 3477-3488, 2022 06.
Article em En | MEDLINE | ID: mdl-35029032
ABSTRACT
Adult T-cell leukemia/lymphoma (ATL) develops after a long period of human T-cell leukemia virus (HTLV)-1 infection and is associated with host aging in addition to genetic abnormalities in HTLV-1 infected cells. SIRT1 is a histone deacetylase involved in cell cycle and apoptosis. We previously showed the high expression of SIRT1 protein in peripheral blood mononuclear cells from patients with ATL. There have been many reports that SIRT1 inhibitors show tumor-suppressive effects. On the other hand, SIRT1 activator SRT1720 induces the cell death of multiple myeloma and breast cancer cells. However, the effect of SRT1720 on ATL is unknown. This study aimed to evaluate the effect of SRT1720 on cell death in leukemic cell lines in vitro and freshly isolated ATL cells ex vivo and in an ATL in vivo mouse model. SRT1720 reduced cell viability in vitro and ex vivo. Additionally, SRT1720 increased the number of apoptotic cells, as shown by annexin V positive cells, cleaved poly (ADP-ribose) polymerase 1, cleaved caspase-3, and fragmented DNA. SRT1720 also induced mitochondrial outer membrane permeabilization with the generation of mitochondrial reactive oxygen species and autophagy. However, SIRT1 knockdown did not attenuate SRT1720-induced cell death in leukemic cell lines. Finally, SRT1720 treatment decreased the growth of human ATL tumor xenografts in immunodeficient mice. Our study shows that while SRT1720 does not target SIRT1, it induces cell death in ATL cells via apoptosis and autophagy and has antitumor activity.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Leucemia-Linfoma de Células T do Adulto / Compostos Heterocíclicos de 4 ou mais Anéis Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Leucemia-Linfoma de Células T do Adulto / Compostos Heterocíclicos de 4 ou mais Anéis Idioma: En Ano de publicação: 2022 Tipo de documento: Article