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TAS-116 (pimitespib), a heat shock protein 90 inhibitor, shows efficacy in preclinical models of adult T-cell leukemia.
Ikebe, Emi; Shimosaki, Shunsuke; Hasegawa, Hiroo; Iha, Hidekatsu; Tsukamoto, Yoshiyuki; Wang, Yu; Sasaki, Daisuke; Imaizumi, Yoshitaka; Miyazaki, Yasushi; Yanagihara, Katsunori; Hamaguchi, Isao; Morishita, Kazuhiro.
Afiliación
  • Ikebe E; Department of Microbiology, Oita University Faculty of Medicine, Yufu, Japan.
  • Shimosaki S; Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Tokyo, Japan.
  • Hasegawa H; Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
  • Iha H; Department of Laboratory Medicine, Nagasaki University Hospital, Nagasaki, Japan.
  • Tsukamoto Y; Department of Microbiology, Oita University Faculty of Medicine, Yufu, Japan.
  • Wang Y; Department of Molecular Pathology, Oita University Faculty of Medicine, Yufu, Japan.
  • Sasaki D; Department of Microbiology, Oita University Faculty of Medicine, Yufu, Japan.
  • Imaizumi Y; Department of Laboratory Medicine, Nagasaki University Hospital, Nagasaki, Japan.
  • Miyazaki Y; Department of Hematology, Nagasaki University Hospital, Nagasaki, Japan.
  • Yanagihara K; Department of Hematology, Nagasaki University Hospital, Nagasaki, Japan.
  • Hamaguchi I; Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
  • Morishita K; Department of Laboratory Medicine, Nagasaki University Hospital, Nagasaki, Japan.
Cancer Sci ; 113(2): 684-696, 2022 Feb.
Article en En | MEDLINE | ID: mdl-34794206
Adult T-cell leukemia/lymphoma (ATL) is a highly chemoresistant malignancy of peripheral T lymphocytes caused by human T-cell leukemia virus type 1 infection, for which there is an urgent need for more effective therapeutic options. The molecular chaperone heat shock protein 90 (HSP90) plays a crucial role in nuclear factor-κB (NF-κB)-mediated antiapoptosis in ATL cells, and HSP90 inhibitors are new candidate therapeutics for ATL. Accordingly, we investigated the anti-ATL effects of a novel oral HSP90 inhibitor, TAS-116 (pimitespib), and the mechanisms involved in ex vivo and in vivo preclinical models. TAS-116 achieved IC50 values of less than 0.5 µmol/L in 10 ATL-related cell lines and less than 1 µmol/L in primary peripheral blood cells of nine ATL patients; no toxicity was observed toward CD4+ lymphocytes from healthy donors, indicating the safety of this agent. Given orally, TAS-116 also showed significant inhibitory effects against tumor cell growth in ATL cell-xenografted mice. Furthermore, gene expression profiling of TAS-116-treated Tax-positive or -negative cell lines and primary ATL cells using DNA microarray and multiple pathway analysis revealed the significant downregulation of the NF-κB pathway in Tax-positive cells and cell-cycle arrest in Tax-negative cells and primary ATL cells. TAS-116 suppressed the activator protein-1 and tumor necrosis factor pathways in all examined cells. These findings strongly indicate the efficacy of TAS-116, regardless of the stage of ATL progression, and its potential application as a novel clinical anti-ATL therapeutic agent.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirazoles / Benzamidas / Leucemia-Linfoma de Células T del Adulto / Proteínas HSP90 de Choque Térmico / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Cancer Sci Año: 2022 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirazoles / Benzamidas / Leucemia-Linfoma de Células T del Adulto / Proteínas HSP90 de Choque Térmico / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Cancer Sci Año: 2022 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Reino Unido