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 ( AC s) 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 LC 3‐ 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.

Angiotensin receptor blocker telmisartan inhibits cell proliferation and tumor growth of cholangiocarcinoma through cell cycle arrest

“…The main mechanism associated with antitumor effect by telmisartan treatment has been shown to inhibit cell proliferation by inducing apoptosis in various cancer cell lines, including prostate ( 8 ), renal ( 9 ), endometrial ( 6 ) and colon ( 10 ) cancer lines. More recently, telmisartan induced cell cycle arrest in hematologic and non-hematologic malignancies including our study ( 5 , 11 ).…”

“…According to previously controversial clinical studies, the antitumor effect of telmisartan remains inadequately known. Moreover, in previous studies, telmisartan has been shown to inhibit proliferation of various cancer cells ( 31 – 33 ) in vitro and tumor growth in vivo ( 5 – 7 ). However, there are no any studies on antitumor effects of telmisartan CCA date.…”

“…Angiotensin receptor blocker (ARB), telmisartan is widely prescribed drug for the treatment of hypertension and heart failure. It inhibited the growth of adult T-cell leukemia cell ( 5 ), endometrial ( 6 ), and gastric cancer cells ( 7 ) in several studies. The main mechanism associated with antitumor effect by telmisartan treatment has been shown to inhibit cell proliferation by inducing apoptosis in various cancer cell lines, including prostate ( 8 ), renal ( 9 ), endometrial ( 6 ) and colon ( 10 ) cancer lines.…”

Telmisartan inhibits hepatocellular carcinoma cell proliferation in vitro by inducing cell cycle arrest

“…Telmisartan has been shown to inhibit cell proliferation by inducing apoptosis in various cancer cell lines including endometrial ( 12 ), prostate 17), renal ( 18 ) and colon ( 19 ) cancer cell lines. Although telmisartan induces cell cycle arrest in hematological malignancies ( 20 ), few studies have examined the main antitumor effects of telmisartan, other than apoptosis, on cell cycle arrest in non-hematological malignancies. As shown in our previous study, telmisartan inhibits human esophageal adenocarcinoma cell proliferation and tumor growth by inducing cell cycle arrest through the regulation of cell cycle-related proteins via the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway ( 21 ).…”

Formulation and in vitro evaluation of telmisartan nanoparticles prepared by emulsion-solvent evaporation technique

“…[1][2][3] It was reported that TLM has antiproliferative effect on leukemia cell lines and ex vivo peripheral blood monocytes, and also, TLM causes autophagy and apoptosis by caspase activation. 4 Besides being an ARB, TLM is also described as a peroxisome proliferator-activated receptor (PPAR)-gamma activator and in some studies its anti-tumor activity is linked to PPAR-gamma activation. [1][2][3] Intra peritoneal administration of TLM to human endometrial tumor bearing nude mice showed that treatment with TLM inhibited tumor growth significantly.…”