상위피인용논문
- 조회506
Hyung Gyun Kim1*, Tran Thi Hien2*, Eun Hee Han1, Yong Pil Hwang1, Jae Ho Choi1, Keon Wook Kang2, Kwang-il Kwon1, Bong-Hee Kim1, Sang Kyum Kim1, Gye Yong Song1, Tae Cheon Jeong3 and Hye Gwang Jeong1
1Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon,Korea, 2Department of Pharmacy, College of Pharmacy, Chosun University, Gwangju, Korea,and 3College of Pharmacy, Yeungnam University, Kyungsan, Korea
*These authors contributedequally
Correspondence Hye Gwang Jeong, Tae Cheon Jeong
Abstract
BACKGROUND AND PURPOSE
The expression of P‐glycoprotein (P‐gp), encoded by the multidrug resistance 1 (MDR1) gene, is associated with the emergence of the MDR phenotype in cancer cells. We investigated whether metformin (1,1‐dimethylbiguanide hydrochloride) down‐regulates MDR1 expression in MCF‐7/adriamycin (MCF‐7/adr) cells.
EXPERIMENTAL APPROACH|
MCF‐7 and MCF‐7/adr cells were incubated with metformin and changes in P‐gp expression were determined at the mRNA, protein and functional level. Transient transfection assays were performed to assess its gene promoter activities, and immunoblot analysis to study its molecular mechanisms of action.
KEY RESULTS
Metformin significantly inhibited MDR1 expression by blocking MDR1 gene transcription. Metformin also significantly increased the intracellular accumulation of the fluorescent P‐gp substrate rhodamine‐123. Nuclear factor‐κB (NF‐κB) activity and the level of IκB degradation were reduced by metformin treatment. Moreover, transduction of MCF‐7/adr cells with the p65 subunit of NF‐κB induced MDR1 promoter activity and expression, and this effect was attenuated by metformin. The suppression of MDR1 promoter activity and protein expression was mediated through metformin‐induced activation of AMP‐activated protein kinase (AMPK). Small interfering RNA methods confirmed that reduction of AMPK levels attenuates the inhibition of MDR1 activation associated with metformin exposure. Furthermore, the inhibitory effects of metformin on MDR1 expression and cAMP‐responsive element binding protein (CREB) phosphorylation were reversed by overexpression of a dominant‐negative mutant of AMPK.
CONCLUSIONS AND IMPLICATIONS
These results suggest that metformin activates AMPK and suppresses MDR1 expression in MCF‐7/adr cells by inhibiting the activation of NF‐κB and CREB. This study reveals a novel function of metformin as an anticancer agent.
논문정보
- Research article
- 2011년 03월 (BRIC 등록일 2021-02-09)
- 국내 연구진
- 의약학 > 약학
- 120회 이상 인용된 논문
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