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Imidazole 항진균제 약물의 유방암에서의 PI3K-Akt기전을 통한 mTOR억제 효과에 따른 항암기전 연구
- Alternative Title
- Imidazole Antifungal Drugs Induce Cell Death by Suppressing mTOR through PI3K-Akt Inhibition in Human Breast Cancer
- Author(s)
- 박주호
- Alternative Author(s)
- Juho Park
- Advisor
- 김소희
- Department
- 일반대학원 약학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2018-02
- Language
- eng
- Keyword
- Azole계 항진균제; 세포사멸; cell cycle arrest; 오토파지; PI3K-Akt-mTOR 기전
- Alternative Abstract
- Breast cancer is a top woman cancer and an 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 shown the anticancer efficacy in clinical trial. But, its 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 shown 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. And we also checked imidazole of azole drugs blocked the cell cycle in G0/G1 phage by down-controlling the protein levels of cyclin D1, CDK2, and CDK6 and increased p21 and p27 in breast cancer. Further experiments exhibited 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/SQSTM1 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 a new potential therapeutics for breast cancer.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Pharmacy > 3. Theses(Master)
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