VS-5584 as a PI3K/mTOR inhibitor enhances apoptotic effects of subtoxic dose arsenic trioxide via inhibition of NF-KB activity in B cell precursor acute lymphoblastic leukemia

Activation of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway as a survival signaling cascade is a prominent feature of cancers such as acute lymphoblastic leukemia (ALL). In patients with B-cell precursor-ALL (BCP-ALL), the high activity of the pathway correlates with the weak response to anti-leukemic drugs and relapse as a result of downstream prosurvival pathway activation, such as nuclear factor kappa B (NF-kappa B). Recent targeted therapy (PI3K/mTOR inhibitors) in combination with a multifunctional conventional chemotherapeutic drug may be useful for treatment of BCP-ALL patients. In the current study, the potential of a subtoxic dose (0.2 mu M) of arsenic trioxide (ATO) in combination with VS-5584 (a highly potent PI3K/mTOR dual inhibitor) was tested for blocking of the PI3K/Akt/mTOR pathway, inhibition of NF-kappa B activation and induction of apoptosis and cell-cycle arrest. The data indicate that VS-5584 as a PI3K/mTOR inhibitor inhibited cell proliferation and induced apoptosis in NALM-6 cells by means of NF-kappa B transcriptional activity suppression. This apoptotic process markedly increased 72 h after administration of the subtoxic dose of ATO. We also showed that concomitant treatment of VS-5584 and the subtoxic dose of ATO significantly inhibited phosphorylation of NF-kappa B inhibitor alpha (IKB alpha) and S6 ribosomal protein (S6) as the downstream proteins of the PI3K/Akt/mTOR pathway. Combining VS-5584 and a subtoxic dose of ATO also resulted in down expression of the NF-kappa B target genes involved in cell proliferation and survival. These results indicate that incorporation of VS-5584/ATO combination into BCP-ALL therapeutic protocols can improve treatment and the survival of patients.