Chemotherapeutic Effect of Cell-cycle Modulation in Skp2-targeting Strategy for Liver Cancer

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The G1-arrested hepatoma cells by troglitazone (Tro) expressed less MRP2 (cMOAT), suggesting a lower potential in exporting anti-cancer agents from the inner side of the cells. The Tro-treated cells showed an increased expression of Bcl-xL, indicating an increased anti-apoptotic property. When the cells entered into the S phase of the cell cycle, the expression level of MRP2 recovered, contributing to cyto-protection in the period of DNA synthesis. Then, we examined whether or not these findings were specific for the troglitazone treatment, using the other PPARgamma ligand pioglitazone (Pio), CDK inhibitors, and Skp2 siRNA. As a result, Pio did not decrease the expression level of MRP2, showing no synergistic cyto-cidal effect with anti-cancer agents on the hepatoma cells. In contrast, Tro showed the strong synergistic cyto-cidal effect on the hepatoma cells, when combined with anti-cancer agents simultaneously. CKI and Skp2 siRNA induced cell death, showing synergistic anti-cancer effect on the cells. In xenograft model using nude mice, the combination of Tro with anti-cancer agents slightly inhibited the tumor growth ; however, Pio did not. These findings suggested the cell-cycle modulation by PPARgamma ligands did not necessarily strengthen the cytotoxicity of conventional anti-cancer agents. This limitation of the PPARgamma ligands might be attributable to the cell-cycle-specific mechanism for cell protection by expressing Bcl-xL and/or MRP2. Combination of Skp2 siRNA and anti-cancer agents may be more promising.