Blockade of PI3K in acute lymphoblastic leukemia cells to enhance the impact of cyclophosphamide

Abstract

Malignant cells use a variety of signaling pathways to proliferate, evade immune responses, and resist chemotherapy. The PI3K signaling pathway is one of the pathways induced in cancer cells for further growth and resistance to chemotherapy. Therefore, inhibition of this pathway can be considered as an effective method to increase the sensitivity of leukemic cells. Therefore, in this study, we decided to increase the effect of cyclophosphamide by inhibiting PI3K expression in acute lymphoblastic leukemia (ALL) cells. As a novel method, we used biodegradable nanoparticles to transfer PI3K siRNA and cyclophosphamide to leukemic cells. Materials and Methods: : In this study, peripheral blood cells of 10 ALL patients and 10 normal individuals as well as Jurkat and NALM-6 cell lines were used. Trimethyl chitosan-carboxymethyl dextran nanoparticles were used for simultaneous transfer of PI3K siRNA and cyclophosphamide to leukemic cells. The effect of combination therapy on cell survival was investigated using MTT and flow cytometry. Also, the expression of target genes was evaluated using real-time PCR. Results: The synthesized nanoparticles had good physicochemical properties in terms of size and zeta potential, which led to the effective delivery of PI3K siRNA and cyclofifamide to leukemic cells. Simultaneous transfer of PI3K siRNA and cyclofifamide to leukemic cells led to the induction of significant toxicity in leukemic cells and cell lines. Combination therapy also led to a significant induction of apoptosis in cells, which was associated with a change in the pattern of expression of genes involved in the apoptotic process.