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Protein Cell. 2016 Aug;7(8):571-85. doi: 10.1007/s13238-016-0295-0. Epub 2016 Jul 29.

Ursolic acid synergistically enhances the therapeutic effects of oxaliplatin in colorectal cancer.

Author information

1
Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.
2
Cancer Institute of Zhejiang University School of Medicine, Hangzhou, 310009, China.
3
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.
4
Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.
5
Cancer Institute of Zhejiang University School of Medicine, Hangzhou, 310009, China. zhangsz0615@163.com.

Abstract

Oxaliplatin is a key drug in chemotherapy of colorectal cancer (CRC). However, its efficacy is unsatisfied due to drug resistance of cancer cells. In this study, we tested whether a natural agent, ursolic acid, was able to enhance the efficacy of oxaliplatin for CRC. Four CRC cell lines including SW480, SW620, LoVo, and RKO were used as in vitro models, and a SW620 xenograft mouse model was used in further in vivo study. We found that ursolic acid inhibited proliferation and induced apoptosis of all four cells and enhanced the cytotoxicity of oxaliplatin. This effect was associated with down-regulation of Bcl-xL, Bcl-2, survivin, activation of caspase-3, 8, 9, and inhibition of KRAS expression and BRAF, MEK1/2, ERK1/2, p-38, JNK, AKT, IKKα, IκBα, and p65 phosphorylation of the MAPK, PI3K/AKT, and NF-κB signaling pathways. The two agents also showed synergistic effects against tumor growth in vivo. In addition, ursolic acid restored liver function and body weight of the mice treated with oxaliplatin. Thus, we concluded that ursolic acid could enhance the therapeutic effects of oxaliplatin against CRC both in vitro and in vivo, which offers an effective strategy to minimize the burden of oxaliplatin-induced adverse events and provides the groundwork for a new clinical strategy to treat CRC.

KEYWORDS:

colorectal cancer; oxaliplatin; signaling pathways; ursolic acid

PMID:
27472952
PMCID:
PMC4980335
DOI:
10.1007/s13238-016-0295-0
[Indexed for MEDLINE]
Free PMC Article

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