Inhibitory effect of PI3Kδ inhibitor idelalisib on proliferation of human myeloid leukemia cells and the reversal effect on drug resistance to adriamycin.

Objectives: To investigate the effect of adriamycin (ADM), idelalisib or ADM and their combination on cell proliferation and intracellular concentration of ADM, and to explore the reversal effect of idelalisib on drug resistance to ADM.

Methods: The K562 and K562/ADM cells were respectively treated with ADM and idelalisib at different concentrations. The 50% inhibitory concentration (IC) and drug resistance index (RI) of ADM to the 2 kinds of cells were measured by methyl thiazolyl tetrazolium (MTT) assay. Non-cytotoxic dose (cell inhibition rate <5%) of idelalisib in the 2 kinds of cells was determined. Then the K562 and k562/ADM cells were divided into the following groups: a K562 cells + ADM group, a K562 cells + ADM + idelalisib group, a K562/ADM cells + ADM group, and a K562/ADM cells + ADM + idelalisib group. The survival rates, the intracellular ATP levels, and the relative concentration of intracellular ADM were detected by MTT method, ATP bioluminescence assay (ATP-BLA) and flow cytometry (FCM), respectively.

Results: The cell survival rates were significantly decreased in a dose-dependent manner when the cells were treated with different doses of ADM (0.001-10.000 mg/L ). The IC value of ADM in the K562 and K562/ADM cells were 0.2 mg/L and 1.0 mg/L, respectively. The RI value was 5. The cell survival rates were also significantly decreased in a dose-dependent manner when the cells were treated with different doses of idelalisib (1-50 μmol/L). The non-cytotoxic dose of idelalisib in the K562 and K562/ADM cells were 25 μmol/L and 15 μmol/L, respectively. The cell survival rates in the ADM+ idelalisib group was less than that in the ADM group (<0.05)；while there was no statistical difference between the ADM+ idelalisib group and the ADM group in the K562 cells (>0.05). The intracellular ATP level in the K562 cells was about (91.502±0.479) mmol/L, and that in the K562/ADM cells was about (24.311±0.349) mmol/L. The intracellular ATP level in the ADM+ idelalisib group in the K562/ADM cells was less than that in the ADM group (<0.05); but there was no statistical difference between the ADM + idelalisib group and the ADM group in the K562 cells (>0.05). The absorption of intracellular ADM in the ADM + idelalisib group in the K562/ADM cells was more than that in the ADM group (<0.05); but there was no statistical difference in the K562 cells between the 2 groups (>0.05). The exclusion of intracellular ADM in the ADM + idelalisib group in the K562/ADM cells was less than that in the ADM group (<0.05 or <0.01)；but there was no statistical difference in the K562 cells between the 2 groups (>0.05).

Conclusions: Idelalisib exerts effect on inhibition of the proliferation in myeloid leukemia K562 and K562/ADM cells, which may partially reverse the drug resistance of K562/ADM cells to ADM. The mechanisms for the effect of idelalisib may be related to increasing the accumulation of ADM and inducing the cell apoptosis in the K562 and K562/ADM cells.