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

Content Provider	Europe PMC
Author	Shan, Jian-zhen Xuan, Yan-yan Zhang, Qi Huang, Jian-jin
Copyright Year	2016
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.
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ISSN	16731581
Volume Number	17
PubMed Central reference number	PMC5018614
Issue Number	9
PubMed reference number	27604859
Journal	Journal of Zhejiang University. Science. B [J Zhejiang Univ Sci B]
e-ISSN	18621783
DOI	10.1631/jzus.b1600266
Language	English
Publisher	Zhejiang University Press
Publisher Date	2016-09-01
Publisher Place	Hangzhou
Access Restriction	Open
Rights License	Copyright © Zhejiang University and Springer-Verlag Berlin Heidelberg 2016
Subject Keyword	Ursolic acid Colon cancer Hypoxia-inducible factor-1α (HIF-1α) Multidrug resistance gene 1 (MDR1) Drug resistance
Content Type	Text
Resource Type	Article
Subject	Veterinary Medicine Biochemistry, Genetics and Molecular Biology Pharmacology, Toxicology and Pharmaceutics