A novel histone deacetylase inhibitor, FK228, is a promising anticancer agent and has been proposed to modulate intracellular signaling, in addition to regulating gene transcription. We evaluated the effect of this agent on Akt-mediated signaling in relation to its cytotoxic activity using lung adenocarcinoma cell lines. Based on MTT assay and the appearance of cleaved poly (ADP-ribose) polymerase (PARP), we regarded A549 and PC14 cells as relatively sensitive and resistant cell lines, respectively. In A549 cells, FK228 suppressed the phosphorylation of Akt at Ser-473 and glycogen synthase kinase-3 without affecting these protein levels, indicating inhibition of the Akt-mediated signaling pathway. On the other hand, in PC14 cells, these biochemical reactions were not detected after treatment with FK228. The combination of FK228 and a phosphatidylinositol 3-kinase (PI3K)/Akt pathway inhibitor, LY294002, was determined to be synergistically cytotoxic in PC14 cells by isobologram analysis. This synergistic effect was attributable to the enhancement of apoptosis, as judged by flow cytometric analysis, and the appearance of cleaved PARP. The combination of FK228 with UCN-01, another PI3K/Akt pathway inhibitor, also exerted a synergistic effect. We concluded that FK228 suppresses the PI3K/Akt signaling pathway in a cell-specific manner, and this effect is a determinant of sensitivity to FK228.

Related Articles