Involvement of c-Jun N-terminal kinase in reversal of multidrug resistance of human leukemia cells in hypoxia by 5-bromotetrandrine

Abstract

5-Bromotetrandrine (BrTet), a candidate multidrug resistance (MDR) modulator, is a potential compound for use in cancer therapy when combined with anticancer agents such as daunorubicin (DNR) and paclitaxel. The purposeof this study was to investigate the mechanism of reversal of P-glycoprotein (P-gp)-mediated MDR by BrTet and the involvement of the c-Jun N-terminal kinase (JNK)/c-Jun signaling pathway in both adriamycin-sensitive K562 and adriamycin-resistant K562 (KA) leukemia cells in hypoxia. The combination of BrTet and DNR decreased both phosphorylated JNK1/2 and MDR1/P-gp levels under hypoxic conditions. Furthermore, a pharmacological inhibitor of JNK, SP600125, or small interfering RNA (siRNA) oligonucleotides to both JNK1 and JNK2 reversed BrTet- or DNR-induced JNK phosphorylation and MDR1/P-gp levels. We further demonstrated that the decreased JNK phosphorylation and MDR1/P-gp levels were associated with a significant increase in intracellular accumulation of DNR, which dramatically enhanced the sensitivity of drug-resistant KA cells to DNR, and led to cellular apoptosis through activation of the caspase-3 pathway. It is concluded that using BrTet in combination with other chemotherapeutic agents and pharmacological inhibitors of JNK can abrogate the P-gp-induced MDR in adriamycin-resistant K562 cells, which has potential clinical relevance in cancer therapy for chemotherapeutic-resistant human leukemia.

Keywords::

• C-Jun NH₂-terminal kinase
• hypoxia
• multidrug resistance
• 5-bromotetrandrine

View retraction statement:

Wei Zhang, Bao-an Chen, Jun-fei Jin, You-ji He, and Yi-qi Niu, Involvement of c-Jun N-terminal kinase in reversal of multidrug resistance of human leukemia cells in hypoxia by 5-bromotetrandrine. November 2013;54(11):2506–2516. http://dx.doi.org/10.3109/10428194.2013.776681

This article refers to:

Wei Zhang, Bao-an Chen, Jun-fei Jin, You-ji He, and Yi-qi Niu, Involvement of c-Jun N-terminal kinase in reversal of multidrug resistance of human leukemia cells in hypoxia by 5-bromotetrandrine. November 2013;54(11):2506–2516. http://dx.doi.org/10.3109/10428194.2013.776681

Acknowledgements

This work was financially supported by National Key Basic Research Program 973 of China (No. 2010CB732404), the National Natural Science Funds of the People's Republic of China (No. 81170492) and Key Medical Disciplines of Jiangsu Province (2011–2012).

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