Exploring brusatol as a new anti-pancreatic cancer adjuvant: biological evaluation and mechanistic studies
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Zheng Lu1,2,4, Zheng-Quan Lai1, Albert W.N. Leung1, Po Sing Leung3, Zhao-Shen Li2 and Zhi-Xiu Lin1
1School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, China
2Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai, China
3School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, China
4Liver Cirrhosis Diagnosis and Treatment Center, Beijing 302 Hospital, Beijing, China
Zhi-Xiu Lin, email: [email protected]
Keywords: pancreatic cancer, brusatol, gemcitabine, 5-fluorouracil, combination therapy
Received: September 24, 2016 Accepted: April 17, 2017 Published: May 10, 2017
Pancreatic cancer is highly resistant to chemotherapeutic agents and is known to have a poor prognosis. The development of new therapeutic entities is badly needed for this deadly malignancy. In this study, we demonstrated for the first time that brusatol, a natural quassinoid isolated from a Chinese herbal medicine named Bruceae Fructus, possessed potent cytotoxic effect against different pancreatic adenocarcinoma cell lines. Its anti-pancreatic cancer effect was comparable to that of the first-line chemotherapeutic agents such as gemcitabine and 5-fluorouracil, with a more favorable safety profile. In addition, brusatol showed a synergistic anti-proliferative effect toward PANC-1 and Capan-2 cell lines when combined with gemcitabine or 5-fluorouracil. The results of flow cytometry suggested that brusatol combination treatment with gemcitabine or 5-fluorouracil was able to cause cell cycle arrest at G2/M phase, and accentuate apoptosis in PANC-1 cells. Moreover, brusatol deactivated gemcitabine/5-fluorouracil-induced NF-κB activation. Western blot analysis and qRT-PCR results showed that brusatol significantly down-regulated the expression of vimentin and Twist, and markedly stimulated the expression of E-cadherin, the key regulatory factors of the epithelial-mesenchymal transition process. Furthermore, treatment with combination of brusatol and gemcitabine or 5-fluorouracil significantly reduced in vivo tumor growth when compared with treatment of either brusatol or gemcitabine/5-fluorouracil alone. Taken together, these results have amply demonstrated that brusatol is a potent anti-pancreatic cancer natural compound, and the synergistic anti-pancreatic cancer effects of brusatol and gemcitabine/5-fluorouracil observed both in vitro and in vivo are associated with the suppression of epithelial-mesenchymal transition process, indicating that brusatol is a promising adjunct to the current chemotherapeutic regimen.
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