Combined Therapy of ATRA and Imatinib Mesylate Decreases BCR-ABL and ABCB1/MDR1 Expression Through Cellular Differentiation in a Chronic Myeloid Leukemia Model

Abstract

Background/Aim: Chronic Myeloid Leukemia (CML) is a clonal myeloproliferative disease, and a major challenge for the eradication of CML is to understand the cause of the permanence of minimal residual disease (DRM). This work aimed to induce the maturation of leukemic stem cells with All-trans-retinoic acid (ATRA), making them sensitive to treatment with Imatinib (IM). Materials and Methods: K562 cells were treated with IM and with the combined therapy of ATRA together with IM for 48 and 72 h. The expression of BCR-ABL gene and multidrug resistance gene ABCB1 were evaluated using RT-qPCR. Results: The combined ATRA and IM therapy showed a discreet cell differentiation pattern, evidenced by the panoptic morphology analysis at 48 and 72 h of treatment. The BCR-ABL expression showed no statistical difference when treated alone with IM, however in combination with ATRA, the expression was statistically significant in 48 and 72 h (p≤0.0001) and when the treatment groups were compared to each other (p≤0.001). The ABCB1 gene expression showed a decrease in isolated IM therapy (p≤0.05) and in the combination in 48 and 72 h (p≤0.0001). Conclusion: Combined ATRA and IM therapy was shown to be effective in decreasing BCR-ABL and ABCB1 genes, possibly through the differentiation of blast cells, demonstrating that the therapy could be potentially effective in the blast crisis of the disease and for those patients who develop resistance to available CML treatments.

miR‑let‑7c‑3p targeting on Egr‑1 contributes to the committed differentiation of leukemia cells into monocyte/macrophages

“…At present, the treatment of leukemia is mainly based on the combination of chemotherapy and targeted therapy, but there are obvious side effects and a high recurrence rate. The differentiation induction therapy represented by all-trans retinoic acid is one of the best methods for the treatment of leukemia (9)(10)(11); in that, the leukemia cells are induced to differentiate into mature promyelocytes by all trans retinoic acid (ATRA) and their malignant proliferation is inhibited. It is precisely because of this selective effect on leukemia cells that it does not affect normal hematopoietic and immune functions, making it a research hotspot (12)(13)(14)(15).…”

“…Compared with traditional chemotherapy, induced differentiation therapy has become an ideal method for the treatment of leukemia due to its non-toxic side effects (7,8). However, so far, only patients with acute promyelocytic leukemia could get the complete remission induced by differentiation-inducing drugs such as all-trans retinoic acid; other types of leukemia have not benefited from them (9)(10)(11). Therefore, it is necessary to actively explore new intervention targets and corresponding targeted drugs on the basis of in-depth exploration of the key mechanisms of leukemia differentiation disorders.…”

KIAA1429 regulates the expression of RAB27B in a m6A YTHDF1 axis-dependent manner and promotes the progression of chronic myeloid leukemia, serving as a potential therapeutic target

“…ATRA reduces the DNA damage repairing and inhibits the acquiring of Bcr/Abl1 mutation during the treatment of CML, consequently reducing the adaptive drug resistance in CML [48,49] . These results further veri ed the reliability of our previous ndings on KIAA1429, and suggested that inhibiting KIAA1429 could be a potential effective target for treating CML-BC or such with drug resistance.…”

Novel Dicarboximide BK124.1 Breaks Multidrug Resistance and Shows Anticancer Efficacy in Chronic Myeloid Leukemia Preclinical Models and Patients’ CD34+/CD38− Leukemia Stem Cells

“…Upregulation of MDR1 causes cross-resistance to many anticancer agents and thus could impact other available therapy options [ 23 ]. Therefore, researchers endeavor to develop novel pharmacological approaches to prevent or to overcome MDR1 in CML [ 24 , 25 ].…”