Pan-HDAC inhibitor panobinostat, as a single agent or in combination with PI3K inhibitor, induces apoptosis in APL cells: An emerging approach to overcome MSC-induced resistance.

Abstract

The emergence of the drugs targeting epigenetic alterations has brought an optimistic outlook for cancer patients and probably put an end into the devastating effects of the disease. Given to the prominent involvement of histone deacetylase (HDAC) enzymes in the formation of neoplastic nature of acute promyelocytic leukemia (APL), this study was aimed to evaluate the suppressive effect of pan-HDAC inhibitor panobinostat on both NB4 and primary APL patients cells, either in the context of mono- or co-culture with mesenchymal stem cells (MSC). Panobinostat effectively reduced the survival of APL cells; however, as compared to NB4, the viability of primary cells was inhibited at higher concentrations. Our results also showed that although HDAC inhibition could merely block the survival signals transduced from MSC, the presence of PI3K inhibitor could robustly reinforce panobinostat cytotoxicity; suggesting that MSC-induced activation of PI3K may attenuate, at least partly, the efficacy of HDAC inhibition in APL cells. In addition, cellular and molecular investigations on NB4 revealed that not only panobinostat induced p21-mediated G1 arrest and ROS-mediated apoptosis, but also exerted a superior cytotoxicity when combined with c-Myc and autophagy inhibitors. Last but not least, we found that panobinostat combined with arsenic trioxide (ATO) prompted a synergistic effect and provided an improved therapeutic value in NB4; proposing that the abrogation of HDAC using panobinostat might be a befitting approach in APL, either as a single agent or in a combined-modal strategy.