Andrographolide reversed 5-FU resistance in human colorectal cancer by elevating BAX expression

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• 作者：Weicheng Wang^a ; ¹ ; Wenjie Guo^b ; ¹ ; Lele Li^a ; ¹ ; Zan Fu^a ; Wen Liu^b ; Jian Gao^b ; Yongqian Shu^a ; Qiang Xu^b ; ^{molpharm@163.com" class="auth_mail" title="E-mail the corresponding author} ; Yang Sun^b ; ^{yangsun@nju.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Yanhong Gu^a ; ^{guyhphd@163.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Andrographolide ; BAX ; 5-FU-resistant ; Human colorectal cancer
• 刊名：Biochemical Pharmacology
• 出版年：2016
• 出版时间：1 December 2016
• 年：2016
• 卷：121
• 期：Complete
• 页码：8-17
• 全文大小：4206 K

文摘

5-FU is the first line therapy for colorectal cancer, however, treatment effect is often hampered by the development of drug resistance or toxicity at high doses. Andrographolide is a natural diterpenoid from Andrographis paniculata which has anti-bacterial, anti-antiviral and anti-inflammation activities. In the current study, we test the hypothesis that Andrographolide reverses 5-FU resistance in colorectal cancer and examine the underlying mechanism. In vitro and vivo studies indicated that Andrographolide treatment significantly re-sensitizes HCT116/5-FUR cells (HCT116 cells which are 5-FU resistant) to cytotoxicity of 5-FU. Mechanism analysis showed that Andrographolide/5-FU co-treatment elevated apoptosis level of HCT116/5-FUR cells with highly increased level of BAX. By using biotin-Andrographolide pull down and cellular thermal shift assay, we found out that Andrographolide can directly target to BAX. Andrographolide-BAX interaction prevented BAX degradation, enhancing mitochondria-mediated apoptosis thus reversed 5-FU resistance while BAX silence diminished this effect. Further, by analyzing patient samples who received 5-FU involved chemotherapy, we found that expression level of BAX is correlated with PFS. Our results here provide a novel combination treatment strategy, especially for patients with 5-FU-resistant tumors expressing low level of BAX. Meanwhile, we also proposed that BAX expression may be a predicted and prognosis marker of 5-FU involved chemotherapy.