title: Angiotensin II type 1 receptor blocker telmisartan induces apoptosis and autophagy in adult T-cell leukemia cells.
abstract: Adult T-cell leukemia/lymphoma (ATL), an aggressive T-cell malignancy that develops after long-term infection with human T-cell leukemia virus (HTLV-1), requires new treatments. Drug repositioning, reuse of a drug previously approved for the treatment of another condition to treat ATL, offers the possibility of reduced time and risk. Among clinically available angiotensin II receptor blockers, telmisartan is well known for its unique ability to activate peroxisome proliferator-activated receptor-γ, which plays various roles in lipid metabolism, cellular differentiation, and apoptosis. Here, telmisartan reduced cell viability and enhanced apoptotic cells via caspase activation in ex vivo peripheral blood monocytes from asymptomatic HTLV-1 carriers (ACs) or via caspase-independent cell death in acute-type ATL, which has a poor prognosis. Telmisartan also induced significant growth inhibition and apoptosis in leukemia cell lines via caspase activation, whereas other angiotensin II receptor blockers did not induce cell death. Interestingly, telmisartan increased the LC3-II-enriched protein fraction, indicating autophagosome accumulation and autophagy. Thus, telmisartan simultaneously caused caspase activation and autophagy. A hypertension medication with antiproliferation effects on primary and leukemia cells is intriguing. Patients with an early diagnosis of ATL are generally monitored until the disease progresses; thus, suppression of progression from AC and indolent ATL to acute ATL is important. Our results suggest that telmisartan is highly effective against primary cells and leukemia cell lines in caspase-dependent and -independent manners, and its clinical use may suppress acute transformation and improve prognosis of patients with this mortal disease. This is the first report demonstrating a cell growth-inhibitory effect of telmisartan in fresh peripheral blood mononuclear cells from leukemia patients.
authors.affiliation: Department of Biochemistry Faculty of Pharmaceutical Sciences Fukuoka University Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kozako
authors.affiliation: Department of Biochemistry Faculty of Pharmaceutical Sciences Fukuoka University Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Soeda
authors.affiliation: Department of Hematology and Immunology Kagoshima University Hospital Japan; Division of Hematology and Immunology School of Medical and Dental Sciences Center for Chronic Viral Diseases Graduate Kagoshima University Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Yoshimitsu
authors.affiliation: Department of Hematology and Immunology Kagoshima University Hospital Japan; Division of Hematology and Immunology School of Medical and Dental Sciences Center for Chronic Viral Diseases Graduate Kagoshima University Japan.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Arima
authors.affiliation: Division of Hematology and Immunology School of Medical and Dental Sciences Center for Chronic Viral Diseases Graduate Kagoshima University Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Kuroki
authors.affiliation: Department of Rheumatology and Clinical Immunology Kumamoto University Hospital Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Hirata
authors.affiliation: Faculty of Sports and Health Science Fukuoka University Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Department of Pharmaceutical Care and Health Sciences Faculty of Pharmaceutical Sciences Fukuoka University Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Imakyure
authors.affiliation: Department of Biochemistry Faculty of Pharmaceutical Sciences Fukuoka University Japan.
authors.forename: Nanako
authors.initials: N
authors.lastname: Tone
authors.affiliation: Department of Biochemistry Faculty of Pharmaceutical Sciences Fukuoka University Japan.
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Honda
authors.affiliation: Department of Biochemistry Faculty of Pharmaceutical Sciences Fukuoka University Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Soeda
keywords: adult T‐cell leukemia/lymphoma; apoptosis; autophagy; drug repositioning; human T‐cell leukemia virus‐1; telmisartan