Application of ZnO/CNT@Fe3O4 nanocomposite in amplifying the anti-leukemic effect of imatinib: a novel strategy to adjuvant therapy in chronic myeloid leukemia

The advent of tyrosine kinase inhibitors (TKI) in the therapeutic protocols of chronic myeloid leukemia (CML) sparked a flame of hope for patients to finally reach to the milestone of the complete remission. However, by the different mutations bypassing the effectiveness of Imatinib, a powerful impetus has emerged to bring more efficient agents into the field of treatment. The results of the present study declared that the companionship of our synthesized ZnO/CNT@Fe3O4 nanocomposite with Imatinib was able to more efficiently decrease the survival of CML-derived K562 cells probably through inducing reactive oxygen species (ROS)-dependent apoptosis. We also found a superior cytotoxicity in the presence of a well-known autophagy inhibitor, indicating that the apoptotic effect of this treatment was probably enhanced through the suppression of autophagy. Investigating the molecular mechanisms involved in the growth-suppressive effect of ZnO/CNT@Fe3O4-plus-Imatinib clarified that the up-regulation of SIRT1 ceased the progression of the cell cycle, foremost by increasing the expression of p21 and p27 cyclin-dependent kinase inhibitors. Notably, we reported for the first time that either direct or indirect suppression of c-Myc resulted in an enhanced anti-leukemic effect; suggesting that the overexpression of c-Myc could play a contributory role in attenuating the efficacy of ZnO/CNT@Fe3O4-plus-Imatinib in K562. Given to the established efficacy of ZnO/CNT@Fe3O4 in CML cells, our preclinical results suggest that the application of this nanocomposite is an appealing strategy to boost the anti-leukemic effect of TKIs, which should be further studied in combination with other anti-cancer agents either in hematologic malignancies or solid tumors.