Combinational effect of a geranylgeranyltransferase-I inhibitor and PKC inhibitor on human oral squamous cell carcinoma

ObjectiveGeranylgeranyltransferase I (GGTase I) is required for posttranslational modification of oncogenic proteins of the Ras family. Protein kinase C (PKC) is a family of serine/threonine kinases known to play critical roles in cell proliferation, differentiation, and apoptosis. The combined effect of GGTase I inhibitors (GGTIs) and PKC inhibitors was examined.MethodsThe effect of GGTIs and PKC inhibitors on the growth of oral squamous cell carcinoma (SCC) cells was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and synergy was determined by Drewinko's fraction method. The cell cycle was analyzed by flow cytometry and DNA fragmentation was detected by agarose gel electrophoresis.ResultsCombinations of GGTIs and PKC inhibitors exhibited an additive or synergistic effect. When GGTI-298 or GGTI-2147 was combined with the PKC inhibitor safingol, a synergistic effect was observed. The combination of GGTI-298 and safingol at these concentrations resulted in apoptotic cell death showing DNA fragmentation, although each inhibitor alone did not.ConclusionGGTI-298 and safingol inhibited cell growth synergistically and increased the number of apoptotic cells. Safingol may be a candidate for the treatment of oral SCC with GGTIs.