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Combined Therapy of ATRA and Imatinib Mesylate Decreases BCR-ABL and ABCB1/MDR1 Expression Through Cellular
Camila Albuquerque Pinto1, Adrhyann Jullyanne DE Sousa Portilho2, Maritza Cavalcante Barbosa3
1Human Cytogenetics Laboratory, Biological Science Institute, Federal University of Pará, Belém, Brazil.
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.
Insights
This study combined All-trans-retinoic acid (ATRA) with Imatinib (IM) to treat Chronic Myeloid Leukemia (CML). The combination therapy effectively reduced BCR-ABL and ABCB1 gene expression, suggesting a potential new treatment strategy for CML.
Area of Science:
- Hematology
- Molecular Biology
- Oncology
Background:
- Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm.
- Minimal residual disease (MRD) poses a significant challenge in CML eradication.
- Understanding the persistence of MRD is crucial for effective CML treatment.
Purpose of the Study:
- To investigate the potential of All-trans-retinoic acid (ATRA) in inducing leukemic stem cell maturation.
- To enhance the sensitivity of CML cells to Imatinib (IM) treatment.
- To evaluate the combined therapeutic effect of ATRA and IM on CML cells.
Main Methods:
- K562 CML cells were treated with Imatinib (IM) alone and in combination with ATRA.
- Treatments were administered for 48 and 72 hours.
- Gene expression of BCR-ABL and the multidrug resistance gene ABCB1 was quantified using RT-qPCR.
Main Results:
- Combined ATRA and IM therapy induced noticeable cell differentiation.
- BCR-ABL expression was significantly reduced by the combination therapy at 48 and 72 hours (p≤0.0001).
- ABCB1 gene expression decreased significantly with both IM monotherapy (p≤0.05) and combined therapy (p≤0.0001).
Conclusions:
- Combined ATRA and IM therapy demonstrates efficacy in reducing BCR-ABL and ABCB1 gene expression.
- This effect is potentially mediated by the differentiation of blast cells.
- The combination therapy may offer a promising approach for CML blast crisis and treatment-resistant cases.
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