The phosphatidylinositol 3‐kinases ( PI 3 K ) inhibitor GS ‐1101 synergistically potentiates histone deacetylase inhibitor‐induced proliferation inhibition and apoptosis through the inactivation of PI 3 K and extracellular signal‐regulated kinase pathways

Summary Previously, we showed that inhibition of the protein kinase C β ( PKC β)/ AKT pathway augments engagement of the histone deacetylase inhibitor ( HDI )‐induced apoptosis in lymphoma cells. In the present study, we investigated the cytotoxicity and mechanisms of cell death induced by the delta isoform‐specific phosphatidylinositide 3‐kinase ( PI 3 K ) inhibitor, GS ‐1101, in combination with the HDI , panobinostat ( LBH 589) and suberoylanilide hydroxamic acid ( SAHA ). Lymphoma cell lines, primary non‐ H odgkin L ymphoma ( NHL ) and chronic lymphocytic leukaemia ( CLL ) cells were simultaneously treated with the HDI , LBH 589 and GS ‐1101. An interaction of the LBH 589/ GS ‐1101 combination was formally examined by using various concentrations of LBH 589 and GS ‐1101. Combined treatment resulted in a synergistic inhibition of proliferation and showed synergistic effect on apoptotic induction in all tested cell lines and primary NHL and CLL cells. This study indicates that interference with PI 3 K signalling dramatically increases HDI ‐mediated apoptosis in malignant haematopoietic cells, possibly through both AKT ‐dependent or AKT ‐ independent mechanisms. Moreover, the increase in HDI ‐related apoptosis observed in PI 3 K inhibitor‐treated cells appears to be related to the disruption of the extracellular signal‐regulated kinase ( ERK ) signalling pathway. This study provides a strong rational for testing the combination of PI 3 K inhibitors and HDI in the clinic.