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CLC number: R735.3+5

On-line Access: 2016-09-07

Received: 2016-06-10

Revision Accepted: 2016-08-08

Crosschecked: 2016-08-11

Cited: 2

Clicked: 1805

Citations:  Bibtex RefMan EndNote GB/T7714

 ORCID:

Jian-zhen Shan

http://orcid.org/0000-0002-6404-0496

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Journal of Zhejiang University SCIENCE B 2016 Vol.17 No.9 P.672-682

http://doi.org/10.1631/jzus.B1600266


Ursolic acid sensitized colon cancer cells to chemotherapy under hypoxia by inhibiting MDR1 through HIF-1α


Author(s):  Jian-zhen Shan, Yan-yan Xuan, Qi Zhang, Jian-jin Huang

Affiliation(s):  Department of Medical Oncology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China; more

Corresponding email(s):   huangjianjin18@163.com

Key Words:  Ursolic acid, Colon cancer, Hypoxia-inducible factor-1α, (HIF-1α, ), Multidrug resistance gene 1 (MDR1), Drug resistance


Jian-zhen Shan, Yan-yan Xuan, Qi Zhang, Jian-jin Huang. Ursolic acid sensitized colon cancer cells to chemotherapy under hypoxia by inhibiting MDR1 through HIF-1α[J]. Journal of Zhejiang University Science B, 2016, 17(9): 672-682.

@article{title="Ursolic acid sensitized colon cancer cells to chemotherapy under hypoxia by inhibiting MDR1 through HIF-1α",
author="Jian-zhen Shan, Yan-yan Xuan, Qi Zhang, Jian-jin Huang",
journal="Journal of Zhejiang University Science B",
volume="17",
number="9",
pages="672-682",
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publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B1600266"
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%T Ursolic acid sensitized colon cancer cells to chemotherapy under hypoxia by inhibiting MDR1 through HIF-1α
%A Jian-zhen Shan
%A Yan-yan Xuan
%A Qi Zhang
%A Jian-jin Huang
%J Journal of Zhejiang University SCIENCE B
%V 17
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%D 2016
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B1600266

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T1 - Ursolic acid sensitized colon cancer cells to chemotherapy under hypoxia by inhibiting MDR1 through HIF-1α
A1 - Jian-zhen Shan
A1 - Yan-yan Xuan
A1 - Qi Zhang
A1 - Jian-jin Huang
J0 - Journal of Zhejiang University Science B
VL - 17
IS - 9
SP - 672
EP - 682
%@ 1673-1581
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PB - Zhejiang University Press & Springer
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DOI - 10.1631/jzus.B1600266


Abstract: 
Objective: To explore the efficacy of ursolic acid in sensitizing colon cancer cells to chemotherapy under hypoxia and its underlying mechanisms. Methods: Three colon cancer cell lines (RKO, LoVo, and SW480) were used as in vitro models. 5-Fluorouracil (5-FU) and oxaliplatin were used as chemotherapeutic drugs. Cell viability and apoptosis were tested to evaluate the sensitivity of colon cancer cells to chemotherapy. The transcription and expression levels of hypoxia-inducible factor-1α; (HIF-1α;), multidrug resistance gene 1 (MDR1), and vascular endothelial growth factors (VEGF) were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and immunoblotting. Cycloheximide and MG132 were used to inhibit protein synthesis and degradation, respectively. In vitro tube formation assay was used to evaluate angiogenesis. Results: We demonstrated the chemosensitizing effects of ursolic acid with 5-FU and oxaliplatin in three colon cancer cell lines under hypoxia. This effect was correlated to its inhibition of MDR1 through HIF-1α. Moreover, ursolic acid was capable of inhibiting HIF-1α accumulation with little effects on its constitutional expression in normoxia. In addition, ursolic acid also down-regulated VEGF and inhibited tumor angiogenesis. Conclusions: ursolic acid exerted chemosensitizing effects in colon cancer cells under hypoxia by inhibiting HIF-1α accumulation and the subsequent expression of the MDR1 and VEGF.

熊果酸在低氧状态下通过抑制低氧诱导因子1α(HIF-1α)和多药耐药基因1(MDR1)对结肠癌细胞化疗药物增敏的实验研究

目的:探索在低氧状态下熊果酸对结肠癌细胞化疗增敏的作用及其机制。
创新点:首次发现了熊果酸对结肠癌细胞株有化疗增敏作用,这种效果与抑制HIF-1α和MDR1相关。熊果酸在低氧条件下还能抑制肿瘤新生血管生成。
方法:分别在常氧和乏氧状态下,在三种结肠癌细胞株RKO、LoVo和SW480对5-FU和奥沙利铂的细胞增殖和凋亡实验中,观察熊果酸对提高结肠癌细胞化疗的敏感性(图1和2)。通过定量实时聚合酶链反应和免疫印迹评估HIF-1α、MDR1和血管内皮生长因子(VEGF)的基因转录和蛋白表达水平(图3和4)。通过体外血管形成实验来评价熊果酸对新生血管抑制作用(图5)。
结论:熊果酸在乏氧状态下抑制HIF-1α的积累和MDR1的基因和蛋白表达,并抑制新生VEGF的表达,同时对结肠癌细胞化疗有增敏作用。

关键词:熊果酸;结肠癌;低氧诱导因子1α(HIF-1α);多药耐药基因1(MDR1);耐药

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

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