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The cycloartane triterpenoid ADCX impairs autophagic degradation through Akt overactivation and promotes apoptotic cell death in multidrug-resistant HepG2/ADM cells.

Abstract
Multidrug resistance is the main obstacle in cancer chemotherapy. Emerging evidence demonstrates the important role of autophagy in cancer cell resistance to chemotherapy. Therefore, autophagy inhibition by natural compounds may be a promising strategy for overcoming drug resistance in liver cancer cells. Here, we found that ADCX, a natural cycloartane triterpenoid extracted from the traditional Chinese medicine (TCM) source Cimicifugae rhizoma (Shengma), impaired autophagic degradation by suppressing lysosomal cathepsin B (CTSB) expression in multidrug-resistant liver cancer HepG2/ADM cells, thereby leading to autophagic flux inhibition. Moreover, impairing autophagic flux promoted ADCX-induced apoptotic cell death in HepG2/ADM cells. Interestingly, Akt was overactivated by ADCX treatment, which downregulated CTSB and inhibited autophagic flux. Together, our results provide the first demonstration that an active TCM constituent can overcome multidrug resistance in liver cancer cells via Akt-mediated inhibition of autophagic degradation.
AuthorsHaiyan Sun, Maohua Huang, Nan Yao, Jianyang Hu, Yingjie Li, Liping Chen, Nan Hu, Wencai Ye, William Chi-Shing Tai, Dongmei Zhang, Sibao Chen
JournalBiochemical pharmacology (Biochem Pharmacol) Vol. 146 Pg. 87-100 (12 15 2017) ISSN: 1873-2968 [Electronic] England
PMID29074104 (Publication Type: Journal Article)
CopyrightCopyright © 2017 Elsevier Inc. All rights reserved.
Chemical References
  • 25-O-acetyl-7,8-didehydrocimigenol 3-O-xylopyranoside
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Saponins
  • Triterpenes
  • Proto-Oncogene Proteins c-akt
Topics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics, metabolism)
  • Apoptosis (drug effects)
  • Carcinoma, Hepatocellular (drug therapy)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Drug Resistance, Neoplasm
  • Gene Expression Regulation, Neoplastic (drug effects)
  • Humans
  • Liver Neoplasms (drug therapy)
  • Molecular Structure
  • Proto-Oncogene Proteins c-akt (genetics, metabolism)
  • Saponins (chemistry, pharmacology)
  • Triterpenes (chemistry, pharmacology)

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