Effects of azole antifungal drugs in the human breast cancer as cancer therapeutic agents
- 주제(키워드) breast cancer , clotrimazole , ketoconazole , cell proliferation , invasion , MMP 9
- 발행기관 아주대학교
- 지도교수 김소희
- 발행년도 2016
- 학위수여년월 2016. 2
- 학위명 석사
- 학과 및 전공 일반대학원 약학
- 실제URI http://www.dcollection.net/handler/ajou/000000021685
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Breast cancer is a top woman cancer and an incidence rate increases every year. Breast cancer can recur within 5 years and metastasize to lung, liver, brain and bone. Azole antifungal drugs structurally have an imidazole [clotrimazole (CTZ) and ketoconazole (KCZ)] or a triazole [fluconazole (FCZ) and itraconazole (ICZ)] ring. Recently, azole antifungal drugs have shown the anticancer efficacy in clinical trial. However, the effects and antitumor mechanism of the azole drugs are little known. Here, we evaluated the effects of azole drugs, such as cell proliferation, migration and invasion using human breast adenocarcinoma cells (MCF-7 and MDA-MB-231). The concentrations inhibiting the cell growth by 50% (IC50) of CTZ and KCZ were 21.0 and 35.1 μM for MCF-7 cells, and 13.8 and 41.8 μM for MDA-MB-231 cells respectively. Cell motility rate of MDA-MB-231 cells was significantly reduced by CTZ and KCZ. Untreated, CTZ and KCZ groups width was closed by 44.2, 13.6 and 21.8%, respectively, compared 0 h group in MDA-MB-231 cells. Transwell invasion assay revealed that CTZ and KCZ strongly inhibited the invasiveness by 84.4 and 67.8%, respectively, in MDA-MB-231 cells. This was also confirmed by gelatin zymography that CTZ and KCZ inhibited matrix metalloproteinase 9 (MMP 9) by 74.0 and 59.3%, respectively, in MDA-MB-231 cells. Immunoblot analysis has shown that the expression of p53, p27 and cleavage of poly ADP ribose polymerase (PARP) on MCF-7 cells increased and cyclin dependent kinase 4 (CDK 4) on MDA-MB-231 cells decreased by CTZ and KCZ. Interestingly, there were no significant changes by treatment with FCZ and ICZ in both breast cancer cells. In conclusion, only imidazole antifungal drugs, CTZ and KCZ, showed a strong antitumor activity on breast cancer cells through the inhibition of cell proliferation, migration and invasion. We need further to clarify the underlying mechanism of action and structure-activity relationship between imidazole and triazole compounds.
more목차
I. INTRODUCTION 1
II. METHOD 4
A. Cell lines 4
B. Material 4
C. Cell proliferation assay 5
D. Protein extraction and immunoblot analysis 5
E. Wound healing assay 6
F. Cell invasion assay 7
G. Gelatin zymography assay 7
H. Statistical analysis 8
III. RESULTS 9
A. The effects on the cell proliferation 9
B. Immunoblot analysis 12
C. Wound healing assay 14
D. The effects on cell invasion 16
E. Gelatin zymography 18
IV. DISCUSSION 20
V. CONCLUSION 22
REFERENCES 23
KOREAN ABSTRACT 27
