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

Abstract

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.

• Authors: Weicheng Wang, Wenjie Guo, Lele Li, Zan Fu, Wen Liu, Jian Gao, Yongqian Shu, Qiang Xu, Yang Sun, Yanhong Gu
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 121 Pg. 8-17 (Dec 01 2016) ISSN: 1873-2968 [Electronic] England
• PMID: 27693317 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• BAX protein, human
• Diterpenes
• bcl-2-Associated X Protein
• andrographolide
• Fluorouracil

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Cell Survival (drug effects)
• Colorectal Neoplasms (drug therapy, metabolism, pathology)
• Diterpenes (administration & dosage, pharmacology, therapeutic use)
• Drug Resistance, Neoplasm (drug effects)
• Fluorouracil (administration & dosage, pharmacology, therapeutic use)
• HCT116 Cells
• Humans
• Membrane Potential, Mitochondrial (drug effects)
• Mice, Nude
• Up-Regulation
• Xenograft Model Antitumor Assays
• bcl-2-Associated X Protein (genetics, metabolism)