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

Abstract

The advent of tyrosine kinase inhibitors in the therapeutic protocols of chronic myeloid leukemia (CML) was a revolution in the treatment strategies that guaranteed the achievement of complete remission for patients. However, due to different mutations bypassing the efficacy of Imatinib, novel and more effective treatments are indeed required for the treatment of CML. Our study declared that the combination of synthesized ZnO/CNT@Fe3O4 nanocomposite with Imatinib decreased survival of CML-derived K562 cells, probably through inducing reactive oxygen species-mediated apoptosis. We also found improved cytotoxicity in the presence of a well known autophagy inhibitor, indicating that the apoptotic effect of this treatment is enhanced via autophagy suppression. Investigating the molecular mechanisms for the growth-suppressive effect of ZnO/CNT@Fe3O4-plus-Imatinib suggested that up-regulation of SIRT1 ceased cell cycle progression by increasing the expression of p21 and p27 cyclin-dependent kinase inhibitors. Notably, we reported here for the first time that either direct or indirect suppression of c-Myc results in enhanced anti-leukemic efficacy, suggesting that overexpression of c-Myc plays a contributory role in attenuating the efficacy of ZnO/CNT@Fe3O4—Imatinib in K562 cells. Given the promising effect of ZnO/CNT@Fe3O4 in potentiating the anti-cancer effects of Imatinib in K562 cells, our study suggested that nanocomposite could be used as a tool for combined-strategy treatment. However, further in vivo experiments are needed to provide clues for the safety and efficacy of this nanocomposite.