Cryptotanshinone acts synergistically with imatinib to induce apoptosis of human chronic myeloid leukemia cells

Abstract

Imatinib resistance has emerged as a significant clinical problem in chronic myeloid leukemia (CML) treatment. In this study, we investigated the effect and mechanism of combination treatment with imatinib and cryptotanshinone (CPT) in CML cells. Cotreatment with imatinib and CPT showed a significant synergistic killing effect in both imatinib sensitive and resistant CML cell lines, as well as primary CML cells. Furthermore, combination treatment induced apoptosis significantly, as indicated by increases in apoptotic cell fraction and activities of proapoptotic proteins. Subsequent studies revealed that CPT significantly inhibited Bcr/Abl protein expression, as well as phosphorylation expression levels of signal transducer and activator of transcription 3 (STAT3), mammalian target of rapamycin (mTOR) and eukaryotic translation initiation factor 4E (eIF4E), which are critical mediators of Bcr/Abl transformation. Furthermore, CPT in combination with imatinib dramatically decreased the activity of the Bcr/Abl pathway in both K562 and K562-R cells. Our results demonstrated that CPT increased imatinib-induced apoptosis in a Bcr/Abl dependent manner, suggesting a novel strategy for the treatment of CML.

Keywords::

• CPT
• imatinib resistance
• synergism
• Bcr/Abl pathway

Acknowledgements

Funding for this work was provided by the National Natural Science Foundation of China (81202820 and 81303269), Zhejiang Provincial Natural Science Foundation of China (Q12H28005) and Zhejiang Provincial Administration of Traditional Chinese Medicine (2012ZQ006 and 2011ZA081).

Potential conflict of interest:

Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.