title: Increased glutathione and mitogen-activated protein kinase phosphorylation are involved in the induction of doxorubicin resistance in hepatocellular carcinoma cells.
abstract: OBJECTIVE
  The human hepatocellular carcinoma (HCC) cell line HepG2 can easily acquire resistance to doxorubicin. However, the mechanism of action is unclear.
  
  
  METHODS
  In the present study, we used confocal microscopy, flow cytometry and other methods to reveal the mechanisms by which HepG2 cells acquire doxorubicin resistance.
  
  
  RESULTS
  Our results showed that R-HepG2 cells, a doxorubicin-resistant sub-line of HepG2, exhibited decreased intracellular accumulation of doxorubicin and increased expression of P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 when compared with HepG2 cells. R-HepG2 cells also harbored higher levels of glutathione and increased expression of glutathione peroxidase. Furthermore, we demonstrated that the phosphorylation of mitogen-activated protein kinases (p38 and c-jun-N-terminal kinases), IkBα and CREB were increased in R-HepG2 cells. Specific p38 inhibitor SB203580 decreased P-gp expression. The multi-kinase inhibitor sorafenib tosylate also significantly suppressed the phosphorylation of these proteins and inhibited the expression of P-gp.
  
  
  CONCLUSIONS
  These findings reveal that the drug resistance could be acquired through mitogen-activated protein kinase-dependent upregulation of P-gp. This mechanism protects R-HepG2 cells from the anticancer action of doxorubicin.
authors.affiliation: Sino-America Cancer Research Institute, The Guangdong Medical College, Guangdong             School of Biomedical Sciences             Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Cai-Guo
authors.initials: CG
authors.lastname: Ye
authors.forename: John Hok-Keung
authors.initials: JH
authors.lastname: Yeung
authors.forename: Guo-Liang
authors.initials: GL
authors.lastname: Huang
authors.forename: Ping
authors.initials: P
authors.lastname: Cui
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Yin
authors.initials: Y
authors.lastname: Zou
authors.forename: Xiang-Ning
authors.initials: XN
authors.lastname: Zhang
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: He
authors.forename: Chi-Hin
authors.initials: CH
authors.lastname: Cho