Andrographolide reversed 5-FU resistance in human colorectal cancer by elevating BAX expression.
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.
Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
Weicheng
W
Wang
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
Wenjie
W
Guo
Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
Lele
L
Li
Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
Zan
Z
Fu
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
Wen
W
Liu
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
Jian
J
Gao
Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
Yongqian
Y
Shu
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China. Electronic address: molpharm@163.com.
Qiang
Q
Xu
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China. Electronic address: yangsun@nju.edu.cn.
Yang
Y
Sun
Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China. Electronic address: guyhphd@163.com.
Yanhong
Y
Gu
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004224:Diterpenes / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D045325:HCT116 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008819:Mice, Nude; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
C494826:BAX protein, human; D004224:Diterpenes; D051028:bcl-2-Associated X Protein; C030419:andrographolide; D005472:Fluorouracil
5-FU-resistant; Andrographolide; BAX; Human colorectal cancer