JNK/AP-1 activation contributes to tetrandrine resistance in T-cell acute lymphoblastic leukaemia

• 来源期刊: 中国药理学报（英文版）
• 关键词: T-cell acute lymphoblastic leukaemia Jurkat cells tetrandrine MAPK JNK activator protein 1 multidrug resistance P-gp
• 年，卷（期）: 2017,（8）
• 页码范围: 1171-1183
• 页数: 13页
• 语种: 英文
• DOI: 10.1038/aps.2017.26

摘要

T-cell acute lymphoblastic leukaemia (T-ALL) is a challenging malignancy with a high relapse rate attributed to drug resistance.Tetrandrine (TET),a bisbenzylisoquinoline alkaloid extracted from a Chinese herb,is a potential anti-cancer and anti-leukaemic drug.In this study we investigated the mechanisms of TET resistance in T-ALL cells in vitro.Among the four T-ALL cell lines tested,Jurkat and CEM cells exhibited the lowest and highest resistance to TET with IC50 values at 24 h of 4.31±0.12 and 16.53±3.32 pmol/L,respectively.When treated with TET,the activity of transcription factor activator protein 1 (AP-1) was significantly decreased in Jurkat cells but nearly constant in CEM cells.To avoid cell-specific variation in drug resistance and transcription factor activities,we established a TET-R Jurkat subclone with the estimated IC50 value of 10.90±.92 pmol/L by exposing the cells to increasing concentrations of TET.Interestingly,when treated with TET,TET-R Jurkat cells exhibited enhanced AP-1 and NF-KB activity,along with upregulation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) signaling pathways,whereas the expression of P-gp was not altered.Selective inhibition of JNK but not ERK suppressed AP-1 activity and TET resistance in TET-R Jurkat cells and in CEM cells.These results demonstrate that Jurkat cells acquire TET resistance through activation of the JNK/AP-1 pathway but not through P-gp expression.The JNK/AP-1 pathway may be a potential therapeutic target in relapsed T-ALL.