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.

Anticancer Effects of ZnO/CNT@Fe3O4 in AML-Derived KG1 Cells: Shedding Light on Promising Potential of Metal Nanoparticles in Acute Leukemia

“…The result of our study demonstrated a significant decrease in viability and metabolic activity of AML derived-KG1 cells after treatment with ZnO/CNT@Fe3O4. Many studies revealed that the cytotoxicity of these nanomaterials, at least partially, may be induced as a result of reactive oxygen species (ROS) generation, which in turn can promote apoptosis signaling by inducing the expression of multiple pro-apoptotic members of the Bcl2-family of mitochondria-targeting proteins 14,34 . Interestingly, we found that ZnO/CNT@Fe3O4 induces apoptosis in KG1 cells through elevation of the ratio of the pro-to anti-apoptotic genes via alteration of Bax and Bcl-2 expression.…”

“…Tanino et al reported that ZnO NPs exerts significant cytotoxicity against lung cancer cells while they exhibited less cytotoxic effects on normal lung-derived cells and did not elicit observable adverse effects after intravenous administration 13 . The results of our recent study have demonstrated that ZnO/CNT@Fe3O4 significantly reduced the survival of CML-derived K562 cells through ROS generation and alteration of apoptosis-related genes 14 . The prominent efficacy of NPs against chronic myeloid leukemia cells and lack of an efficient treatment in acute leukemia encouraged us to investigate whether ZnO/CNT@Fe3O4 induces favorable cytotoxicity in AML cells.…”

<i>In Vivo</i> Animal Model Evaluation of a Powerful Oral Nanomedicine for Treating Breast Cancer in BALB/c Mice Using 4T1 Cell Lines without Chemotherapy

“…concentration and cellular viability, whereas smaller NPs are showing greater toxicity. Because there are more pores on the high surface area naturally, more reactions occur on the surface[70] [71]. Due to the inherent photoluminescence properties, which can be useful in biosensing applications, recent studies have reported that ZnO nanomaterials and nanocomposites are considered promising and make them a suitable choice for anticancer medicines.…”