Shimizu Masahito, Suzui Masumi, Deguchi Atsuko, Lim Jin T E, Xiao Danhua, Hayes Julia H, Papadopoulos Kyriakos P, Weinstein I Bernard
Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Clin Cancer Res. 2004 Oct 1;10(19):6710-21. doi: 10.1158/1078-0432.CCR-04-0659.
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 micromol/L acyclic retinoid and 0.01 micromol/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-xL, 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 beta and to stimulate retinoic acid response element-chloramphenicol acetyltransferase activity. A hypothetical model involving concerted effects on p21(CIP1) and retinoic acid receptor beta 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.
肝癌是全球最常见的癌症之一。然而，针对这种疾病的有效化疗药物尚未研发出来。非环状维甲酸，一种新型合成维甲酸，可降低肝癌术后复发率并提高生存率。OSI - 461，一种强效的依西美坦衍生物，可提高细胞内环磷酸鸟苷水平，从而导致蛋白激酶G激活并诱导癌细胞凋亡。在本研究中，我们检测了非环状维甲酸与OSI - 461联合应用于HepG2人肝癌细胞系的效果。我们发现，低至1.0微摩尔/升的非环状维甲酸与0.01微摩尔/升的OSI - 461联合应用对HepG2细胞生长具有协同抑制作用。这两种药物低浓度联合处理还通过诱导Bax和Apaf - 1、降低Bcl - 2和Bcl - xL以及激活caspase - 3、 - 8和 - 9协同诱导HepG2细胞凋亡。OSI - 461增强了非环状维甲酸引起的G0 - G1期阻滞，这两种药物联合应用导致细胞周期蛋白D1蛋白和mRNA表达水平协同降低，抑制细胞周期蛋白D1启动子活性，降低Rb蛋白的过度磷酸化形式水平，诱导细胞内p21(CIP1)蛋白和mRNA水平升高，并刺激p21(CIP1)启动子活性。此外，OSI - 461增强了非环状维甲酸诱导细胞内视黄酸受体β水平升高以及刺激视黄酸反应元件 - 氯霉素乙酰转移酶活性的能力。我们提出了一个涉及对p21(CIP1)和视黄酸受体β表达协同作用的假设模型来解释这些协同效应。我们的结果表明，非环状维甲酸与OSI - 461联合应用可能是人类肝癌及其他可能的恶性肿瘤化学预防和化疗的有效方案。
