Angiotensin II receptor blockers induce autophagy in prostate cancer cells.

Abstract

Angiotensin II receptor blockers (ARBs) are anti-hypertensive drugs that competitively inhibit the binding of angiotensin II to its receptor, resulting in blood vessel dilation and the reduction of blood pressure. These antagonists are also known as sartans, and are a group of pharmaceuticals that possess tetrazole or imidazole groups. In the present study, the anticancer and antimetastatic effects of the ARBs fimasartan, losartan, eprosartan and valsartan on the human prostate cancer PC-3, DU-145 and LNCap-LN3 cell lines were investigated in vitro. The proliferation of the prostate cancer cells was inhibited following treatment with 100 µM ARB. In particular, treatment with fimasartan resulted in marked anti-proliferative activity compared with the other ARBs. With respect to the molecular mechanism of the growth inhibition exhibited by the ARBs, 3-methyladenin (3-MA), an autophagy inhibitor, was revealed to increase the survival rate of PC-3 cells when cell death inhibitors were pretreated with fimasartan. In addition, the ARBs induced autophagy with increased expression levels of autophagy protein (Atg) 5–12, Atg 16-like-1, beclin-1 and microtubule-associated protein 1A/1B-light chain 3 (LC3). Notably, the enhanced expression of LC3-II (a 6.7-fold increase at 72 h) was observed in PC3 cells treated with fimasartan. This was supported by the observation of the time-dependent accumulation of LC3-positive foci in PC-3. In addition, a migration assay indicated that the ARBs induced anti-metastatic effects in PC-3 and DU-145 cells. The aforementioned results suggest that ARBs may induce autophagy-associated cell death and anti-metastatic activity in prostate cancer cells. Thus, ARBs may be a potential medication for patients with prostate cancer and hypertension.