The Superior Cytotoxicity of Dual Targeting of BCR/ABL and PI3K in K562 Cells: Proposing a Novel Therapeutic Potential for the Treatment of CML

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Abstract
Apart from BCR/ABL which is the main player in the pathogenesis of chronic myeloid leukemia (CML), the role of other signaling cascades should not be underestimated especially for the maintenance of leukemic cells survival. The results of the present study indicate that either an isoform-specific or a pan-PI3K inhibitor could potently reduce the survival of CML-derived K562 cells, shedding more light on the involvement of the PI3K axis in the pathogenesis of CML. Of particular interest, the importance of the PI3K pathway in this disease became more evident when we found that there was a more remarkable reduction in the viability of K562 cells when BKM120 was used in combination with imatinib. Moreover, BKM120 robustly enhanced the growth-suppressive effect of imatinib through p21-mediated induction of G2/M cell cycle arrest and induction of apoptotic cell death. Despite the favorable anti-survival effects of the drug combination, these agents failed to induce inhibitory effects on the expression of c-Myc and NF-κB anti-apoptotic target genes. However, the ability of combinational therapy in diminishing K562 cell survival was potentiated either in the presence of 10058-F4 (c-Myc inhibitor) or Bortezomib (proteasome inhibitor), suggestive of the role of both NF-κB and c-Myc in overshadowing the therapeutic value of drugs combination. Taken together, the results of this study showed that inhibition of the PI3K pathway is a suitable approach to enhance the therapeutic value of imatinib in the treatment of CML.
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  • Shahid Beheshti University of Medical Sciences

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