The object of this study was to determine how phosphatidylinositol (PI) signaling pathway is involved in the regulation of cisplatin (DDP) sensitivity. Clonogenic survival assay was used to determine the effect of orobol, a potent PI4-kinase inhibitor, on DDP sensitivity in human ovarian carcinoma 2008 cells. Orobol enhanced sensitivity to DDP in 2008 cells by a factor of 2.1±0.4 (SD)-fold (N=3; P<0.01). Sensitization was specific for proliferating cells. Orobol did not alter DDP sensitivity in quiescent cells. Orobol also produced a 2-fold increase in sensitivity to DDP in proliferating 2008/C13*5.25 DDP-resistant variants. Our studies indicated that orobol-induced sensitization depended on the presence of proliferating cells in G2+M phase of the cell cycle. Orobol did not modulate the cellular accumulation of DDP nor did it alter the CdCl2 sensitivity, suggesting that the amount of platinated-DNA was not changed by orobol treatment. However, orobol rendered 2008 cells resistant to rhodamin 123 by 5.7±1.7 (SD)-fold (N=3, P<0.01). Since sensitivity to rhodamin 123 is indicative of mitochondrial membrane potential, these results imply that mitochondrial alterations may be an important component of the orobol sensitization effect in these cells.

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