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

Objective: Geranylgeranyltransferase 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. Methods: The 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. Results: Combinations 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. Conclusion: GGTI-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. (C) 2012 Asian AOMS, ASOMP, JSOP, JSOMS, JSOM, and JAMI. Published by Elsevier Ltd. All rights reserved.