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Synergistic Effects of Acyclic Retinoid and OSI-461 on Growth Inhibition and Gene Expression in Human Hepatoma Cells

¹ Herbert Irving Comprehensive Cancer Center and ² Division of Medical Oncology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York; and ³ Department of Pathology, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan

Hepatoma is one of the most frequently occurring cancers worldwide. However, effective chemotherapeutic agents for this disease have not been developed. Acyclic retinoid, a novel synthetic retinoid, can reduce the incidence of postsurgical recurrence of hepatoma and improve the survival rate. OSI-461, a potent derivative of exisulind, can increase intracellular levels of cyclic GMP, which leads to activation of protein kinase G and induction of apoptosis in cancer cells. In the present study, we examined the combined effects of acyclic retinoid plus OSI-461 in the HepG2 human hepatoma cell line. We found that the combination of as little as 1.0 µmol/L acyclic retinoid and 0.01 µmol/L OSI-461 exerted synergistic inhibition of the growth of HepG2 cells. Combined treatment with low concentrations of these two agents also acted synergistically to induce apoptosis in HepG2 cells through induction of Bax and Apaf-1, reduction of Bcl-2 and Bcl-x_L, and activation of caspase-3, -8, and -9. OSI-461 enhanced the G₀-G₁ arrest caused by acyclic retinoid, and the combination of these agents caused a synergistic decrease in the levels of expression of cyclin D1 protein and mRNA, inhibited cyclin D1 promoter activity, decreased the level of hyperphosphorylated forms of the Rb protein, induced increased cellular levels of the p21^CIP1 protein and mRNA, and stimulated p21^CIP1 promoter activity. Moreover, OSI-461 enhanced the ability of acyclic retinoid to induce increased cellular levels of retinoic acid receptor ß and to stimulate retinoic acid response element-chloramphenicol acetyltransferase activity. A hypothetical model involving concerted effects on p21^CIP1 and retinoic acid receptor ß expression is proposed to explain these synergistic effects. Our results suggest that the combination of acyclic retinoid plus OSI-461 might be an effective regimen for the chemoprevention and chemotherapy of human hepatoma and possibly other malignancies.

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