Abstract 2327: Azole antifungal drugs induce cell death by suppressing mTOR through PI3K/Akt inhibition in human breast cancer

Abstract

Abstract Breast cancer is a major cancer in women and its incidence rate increases every year. So it needs a perfect treatment. Azole drugs structurally have an imidazole [clotrimazole (CTZ) and ketoconazole (KCZ)] or a triazole [fluconazole (FCZ) and itraconazole (ICZ)]. Recently, azole antifungal drugs have shown anticancer efficacy in clinical trial. However, their antitumor mechanism are vague. Here, we evaluated the effects, as apoptosis, cell arrest, and autophagy and tumor growth using human breast cancer cells. Apoptosis assay showed imidazole-induced cell death, pro-apoptosis maker, as cleaved PARP, cleaved caspase-3, Bax, increased and anti-apoptosis maker, as Bcl-2, decreased by CTZ and KCZ in both MCF-7 and MDA-MB-231 cells. We also checked imidazole of azole drugs blocked the cell cycle in G1 phage by downregulating the protein levels of cyclin D1, CDK2, and CDK6 and increased p21 and p27 in breast cancer. Further experiments showed that azole drugs also induced autophagy through the increased accumulation of LC 3B inside the cells by immunoblot analysis and immunofluorescence staining, increased beclin-1 and decreased p62 protein. With azole decreased that though 3-MA. Azole drugs inhibited PI3K/Akt/mTOR signaling pathway. Tumor growth was also inhibited in nude mice bearing MDA-MB-231 xenograft by CTZ, KCZ and ICZ through the accumulation of LC 3B in tumor xenograft. In conclusion, imidazole antifungal drugs induced apoptosis, cell cycle and autophagy by suppressing mTOR through the regulation of PI3K/Akt pathway in human breast cancer cells, suggesting azole antifungal drugs could be new potential therapeutics for breast cancer. Citation Format: Ju Ho Park, Hyesook Kim, So Hee Kim. Azole antifungal drugs induce cell death by suppressing mTOR through PI3K/Akt inhibition in human breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2327.