Cryptotanshinone enhances the efficacy of Bcr-Abl tyrosine kinase inhibitors via inhibiting STAT3 and eIF4E signalling pathways in chronic myeloid leukaemia

Abstract

Context: A portion of patients with chronic myeloid leukaemia (CML) develop resistance to the Bcr-Abl tyrosine kinase inhibitors (TKIs), limiting the clinical applications. Previous results have demonstrated the synergistic effects between cryptotanshinone (CPT) and imatinib on apoptosis of CML cells in vitro. Objective: To determine the antileukemia effects of CPT and TKIs on the resistant CML cells, and further investigate the effect of combined treatment of CPT and imatinib on tumour growth and apoptosis in the xenograft model and clarify its regulatory mechanisms. Materials and methods: The combination effects of CPT and second-generation TKIs were evaluated in resistant CML cells K562-R. CPT and imatinib were orally administered once daily for 21 days on K562-R xenografts in nude mice (6 per group). Tumour proliferation and apoptosis were examined by Ki-67, PCNA and TUNEL staining. The expression levels of apoptotic markers and activities of STAT3 and eIF4E pathways were determined via immunohistochemistry staining and western blotting analysis. Results: CPT significantly enhanced the antiproliferative effects of TKIs, via triggering cleavages of caspase proteins, and inhibiting activities of STAT3 and eIF4E pathways. The administration of CPT and imatinib dramatically inhibited the tumour growth of xenografts and achieved a suppression of 60.2%, which is 2.6-fold higher than that of single imatinib group. Furthermore, CPT and imatinib increased the apoptotic rates and markedly decreased the phosphorylation levels of STAT3 and eIF4E. Conclusions: Our results demonstrated that CPT could significantly enhance the antileukemia efficacy of TKIs, suggesting the therapeutic potential of CPT to overcome CML resistance.

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“…Cell cycle progression was severely halted in the G1/G0 phase after the STAT3-regulated proteins cyclin D1 and survivin were downregulated [77,78]. Additionally, CPT displayed growth-suppressive effects mediated by STAT3 in chronic myeloid leukemia models [79,80]. These findings suggest that CPT might be a potent antiproliferation medication for managing several types of carcinoma and that STAT3 signaling suppression may play a role in its mode of action.…”

Biological functions and research progress of eIF4E

“…In chronic myeloid leukemia (CML), the expression and phosphorylation level of eIF4E are up-regulated, and the activity of eIF4E in patients with advanced CML is significantly increased. In addition, abnormal activation of eIF4E in leukemic stem cells of CML in blast phase significantly increases the synthesis of b-Catenin (149).…”

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“…The administration of combination of 13 and imatinib induced a 2.6-fold higher suppression of tumour growth of xenografts than those animals treated with imatinib alone. This antiproliferative activity is the consequence of an increase of apoptosis [ 75 ].…”