Angiotensin II receptor blockers valsartan and losartan improve survival rate clinically and suppress tumor growth via apoptosis related to PI3K/AKT signaling in nasopharyngeal carcinoma

• Published in: Cancer Vol. 127; no. 10; pp. 1606 - 1619
• Main Authors: Lin, Yu‐Tsai, Wang, Hung‐Chen, Tsai, Ming‐Hsien, Su, Yan‐Ye, Yang, Ming‐Yu, Chien, Chih‐Yen
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 15.05.2021
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Angiogenesis; Angiotensin; Angiotensin II; angiotensin II receptor blockers; Angiotensin Receptor Antagonists - pharmacology; Anticancer properties; Antitumor activity; Apoptosis; Apoptosis - drug effects; Cancer; Caspase; Cell proliferation; Chemoradiotherapy; Cytochrome; Cytochrome c; Cytochromes; G1 phase; Head & neck cancer; Humans; Hypertension; Losartan - pharmacology; Nasopharyngeal carcinoma; Nasopharyngeal Carcinoma - drug therapy; Nasopharyngeal Carcinoma - metabolism; Nasopharyngeal Neoplasms - drug therapy; Nasopharyngeal Neoplasms - metabolism; Oncology; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Proto-Oncogene Proteins c-akt - metabolism; Radiation therapy; Receptors; Retrospective Studies; Side effects; Signal Transduction - drug effects; Signaling; Survival; Survival Rate; Throat cancer; Treatment Outcome; Valsartan - pharmacology; Xenografts; Xenotransplantation; survival rate; apoptosis; nasopharyngeal carcinoma; angiogenesis; angiotensin II receptor blockers
• ISSN: 0008-543X; 1097-0142; 1097-0142
• DOI: 10.1002/cncr.33391

Background Nasopharyngeal carcinoma (NPC) is a common type of head and neck cancer in Asia. Adverse effects occur in over 90% of NPC patients treated with radiotherapy or chemoradiation. Angiotensin II receptor blockers (ARBs) are commonly used to treat hypertension without serious adverse effects. However, the anticancer activity of ARBs in NPC remains unclear. Methods We investigated the survival impacts of ARBs among NPC patients in a retrospective study. The anticancer effects and related signaling pathways of the ARBs valsartan and losartan were also evaluated in vitro and in vivo. Result A total of 927 patients with NPC who had hypertension were enrolled in the study, 272 (29.3%) of whom received ARBs. Kaplan‐Meier analysis revealed that patients who used ARBs had higher rates of 5‐year overall survival (OS; 87.8% vs 75.1%; P = .002) and disease‐specific survival (DSS; 95.4% vs 77.7%; P < .001) than those who did not receive this treatment. Additionally, ARBs inhibited cell proliferation and induced apoptosis by increasing levels of cleaved caspase‐3, cleaved caspase‐9, and cytochrome C; the cell population in the sub‐G1 phase; and caspase‐3 activity in NPC‐TW01 cells. ARBs inhibited tumor growth and angiogenesis via apoptosis in an NPC xenografts model. Interestingly, ARBs inhibited phosphorylation of PI3K/AKT signaling in vitro and in vivo, which is markedly attributed to their antitumor effects in NPC. Conclusion These data indicate that ARBs not only improve 5‐year OS and DSS among patients with NPC but also exert antiproliferative and antiangiogenesis effects by inducing apoptosis in NPC, supporting that ARBs may be promising agents for treatment of NPC. Use of angiotensin II receptor blockers (ARBs) is associated with improved survival in patients who have nasopharyngeal carcinoma (NPC). The ARBs valsartan and losartan suppress tumor growth and angiogenesis in NPC xenografts.