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

Acta Pharmacol Sin. 2017 Aug;38(8):1171-1183. doi: 10.1038/aps.2017.26. Epub 2017 Jun 12.

Abstract

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 μmol/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 μmol/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-κB 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.

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Benzylisoquinolines / pharmacology*
  • Blotting, Western
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Flow Cytometry
  • Humans
  • Jurkat Cells / drug effects
  • MAP Kinase Signaling System* / physiology
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism

Substances

  • Antineoplastic Agents, Phytogenic
  • Benzylisoquinolines
  • tetrandrine