Abstract
Introduction: Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell malignancy that develops after long-term infection with human T-cell leukemia virus (HTLV-1). Despite the recent advances in chemotherapy, allogeneic hematopoietic stem cell transplantation, and supportive care, the prognosis for patients with acute, lymphoma, or unfavorable chronic subtypes (aggressive ATL) is one of the poorest among hematological malignancies; overall survival at 3 years is only 24 % in the more aggressive subtypes of ATL. In case of favourable chronic or smoldering ATL (indolent ATL), watchful waiting until disease progression has been recommended. Some patients with indolent ATL develop infections during this period. Therefore, urgent need for therapy and prophylaxis of ATL are still required. Recently, drug repositioning offers the possibility of reduced time and risk as several stages common to novel drug discovery and development can be bypassed because repositioning candidates have frequently been through several phases of development for their original indication. With the successful clinical introduction of a number of non-cancer drugs for cancer treatment, drug repositioning now became a potent alternative strategy to discover and develop novel anticancer drug candidates from the existing drug space. On the other hand, the transcription factor PPARγ plays various roles in lipid metabolism, immune response, cellular differentiation and apoptosis. Among clinically available angiotensin II receptor blockers, telmisartan is well known for its unique ability to activate PPARγ. Here, we assessed how telmisartan affects ATL cells from patients and leukemia cell lines.
Methods and Results: Methods used in this study were carried out in accordance with the approved guidelines by the Committees for Ethical Review of Research involving Human Subjects at Kagoshima University. The subjects were examined by standard serological testing for the presence of HTLV-1 and by haematological/Southern blotting analysis for diagnosis of ATL. The classification of ATL was performed according to the criteria of Shimoyama. Telmisartan reduced cell viability and enhanced apoptotic cells in ex vivo peripheral blood monocytes of acute-type ATL, which has a poor prognosis. Telmisartan-induced apoptosis in cells from ATL patients (acute and chronic-type) and asymptomatic HTLV-1 carriers was significantly increased compared with those from healthy donors. Telmisartan also induced significant growth inhibition and apoptosis (Annexin V+ cells and TUNEL) in leukemia cell lines (HTLV-1-related cell lines: S1T, MT-2; Jurkat and HL60), while other angiotensin II receptor blockers, irbesartan and valsartan, did not induce cell death. In apoptosis, several key events occur in mitochondria, including the release of caspase activators, such as apoptosis-induced factor, and loss of mitochondrial transmembrane potential. Telmisartan induced loss of mitochondrial transmembrane potential and generation of reactive oxygen species, although apoptosis-inducing factor level was stable. Telmisartan also inhibited cell growth via caspase activation (caspase-3, 8 and 9) in the leukemia cells. However, treatment with a caspase inhibitor did not inhibit telmisartan-induced cell death. Interestingly, telmisartan increased the LC3-II-enriched protein fraction, indicating autophagosome accumulation as well as autophagy. Thus, Telmisartan simultaneously caused caspase activation and autophagy.
Conclusion: A hypertension medication that has an anti-proliferation effect on leukemia cells is intriguing. These results suggest that telmisartan is highly effective against HTLV-1-infected cells and ATL cells in a caspase-dependent and -independent manner, and its clinical use may suppress the progression from indolent ATL or carrier status to aggressive ATL, and thus improve the prognosis of patients with this fatal disease.
Disclosures
No relevant conflicts of interest to declare.
Cytotoxicity of Trimetrexate against Antifolate-resistant Human T-Cell Leukemia Cell Lines Developed in Oxidized or Reduced Folate
