Sclareol ameliorated ERCC1-mediated cisplatin resistance in A549 human lung adenocarcinoma cells and a murine xenograft tumor model by suppressing AKT-GSK3β-AP1/Snail and JNK-AP1 pathways

Chun Hsu Pan, Shih Yin Chen, Jie Yu Wang, Shu Ping Tsao, Hui Yu Huang, Philip Wei-Chen Chiu, Chieh Hsi Wu

Research output: Contribution to journalArticlepeer-review

Abstract

Cisplatin-based chemotherapy is a common first-line regimen for treating non–small cell lung cancer (NSCLC). However, drug resistance is still a major problem. The purposes of this study were to evaluate whether sclareol can reverse cisplatin resistance and to investigate its possible mechanisms. A549 cells, the human NSCLC cells with inherent cisplatin resistance, were used to investigate synergistic effect of sclareol with cisplatin in cell proliferation and migration as well as its regulatory mechanisms in expression of excision repair cross-complementation group 1 (ERCC1), a cisplatin resistance-associated molecule. Nude mice bearing subcutaneous A549 tumors were applied to investigate synergistic activity of sclareol in anti-tumor. As comparing to the cisplatin alone group, the treatment of cisplatin combined with sclareol significantly suppressed survival rate and cell migration of A549 cells. Besides, sclareol also exhibited suppression in ERCC1 expression by inhibiting AKT-GSK3β-AP1/Snail and JNK-AP1 pathways. Furthermore, the experimental data from in vivo study also demonstrated that the combination group of cisplatin and sclareol showed the greatest anti-tumor activity, whose effect could be partially attributed to sclareol-mediated decrease in intratumoral level of ERCC1 protein. Accordingly, sclareol has potential as an adjuvant for the treatment in NSCLC patients with cisplatin resistance.

Original languageEnglish
Article number109304
JournalChemico-Biological Interactions
Volume332
DOIs
Publication statusPublished - Dec 1 2020

Keywords

  • Cisplatin
  • Drug resistance
  • ERCC1
  • Non-small cell lung cancer
  • Sclareol

ASJC Scopus subject areas

  • Toxicology

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