Apoptin Overexpression Efficiently Amplified Cytotoxic Effects of PI3K Inhibition Using BKM120 in Lymphoblastic Leukemia Cell Lines

Abstract

Purpose: Although the complex structure of acute lymphoblastic leukemia (ALL) andinvolvement of diverse pathways in its pathogenesis have put an obstacle in the way of efficienttreatments, identification of strategies to manipulate the genome of neoplastic cells has madethe treatment prospective more optimistic.Methods: To evaluate whether the transduction of apoptin __a gene encoding a protein thatparticipates in the induction of apoptosis__ could reduce the survival of leukemic cells, wegenerated recombinant lentivirus expressing apoptin, and then, MTT assay, flow cytometricanalysis of DNA content, western blotting, and quantitative reverse transcription polymerasechain reaction (qRT-PCR) were applied.Results: Transduction of apoptin into different leukemic cells was coupled with the reductionin the viability and proliferative capacity of the cells. Among all tested cell lines, Nalm-6 andC8166 were more sensitive to the anti-leukemic property of apoptin. Moreover, we found thatthe transduction of apoptin in the indicated cell lines not only induced G2/M cell cycle arrestbut also induced apoptotic cell death by altering the balance between pro- and anti-apoptotictarget genes. The efficacy of apoptin transduction was not limited to these findings, as wereported for the first time that the overexpression of this gene could potentiate the anti-leukemicproperty of pan PI3K inhibitor BKM120.Conclusion: The results of this study showed that the transduction of apoptin into lymphoblasticleukemia cell lines induced cytotoxic effects and enhanced therapeutic value of PI3K inhibition;however, further investigations are demanded to ascertain the safety and the efficacy of apoptintransduction in patients with ALL.

Keywords

• apoptin
• acute lymphoblastic leukemia (all)
• gene transduction
• pi3k signaling pathway
• bkm120