Department of Pharmacology, School of Preclinical Sciences, Guangxi Medical University, Nanning 530021, P.R. China.
Int J Oncol. 2010 Jul;37(1):111-23.
Green tea catechins have been reported to have antitumor activity. The objective of this study was to examine the effect of catechins on the antitumor efficacy of doxorubicin (DOX) in a murine model for chemoresistant hepatocellular carcinoma (HCC). Epicatechin gallate (ECG) and epigallocatechin gallate (EGCG) are the most abundant polyphenolic compounds in green tea. Here, we show that ECG or EGCG at higher doses had a slight inhibitory effect on cell proliferation in the resistant human HCC cell line BEL-7404/DOX in vitro and in vivo, whereas the administration of DOX with these compounds at lower doses significantly inhibited HCC cell proliferation in vitro and hepatoma growth in a xenograft mouse model, compared with treatment with either agent alone at the same dose. Furthermore, the administration of DOX in combination with ECG or EGCG markedly enhanced intracellular DOX accumulation, which implies that the catechins inhibited P-glycoprotein (P-gp) efflux pump activity. Consistent with these results, the intracellular retention of rhodamine 123, a P-gp substrate, was increased and the level of P-gp was decreased in cells concurrently treated with DOX and ECG or EGCG. EGCG increased topo II expression, but did not alter GST protein levels in tumor xenografts. The expression of MDR1 and HIF-1alpha mRNA was obviously reduced, whereas MRP1 and LRP expression was not changed significantly. These data suggest that tea catechins at non-toxic doses can augment DOX-induced cell killing and sensitize chemoresistant HCC cells to DOX. The chemosensitizing effect of catechins may occur directly or indirectly by reversal of multidrug resistance, involving the suppression of MDR1 expression, or by enhancement of intracellular DOX accumulation, involving inhibition of P-gp function.
绿茶儿茶素有抗肿瘤活性。本研究旨在探讨儿茶素对多柔比星（DOX）在耐药性肝癌（HCC）小鼠模型中抗肿瘤疗效的影响。表儿茶素没食子酸酯（ECG）和表没食子儿茶素没食子酸酯（EGCG）是绿茶中含量最丰富的多酚化合物。在这里，我们表明，ECG 或 EGCG 在较高剂量下对体外耐药人肝癌细胞系 BEL-7404/DOX 及体内细胞增殖有轻微抑制作用，而与单独使用相同剂量的任何一种药物相比，用较低剂量的 DOX 与这些化合物联合使用可显著抑制 HCC 细胞增殖和异种移植小鼠模型中的肝癌生长。此外，DOX 联合 ECG 或 EGCG 给药可显著增加细胞内 DOX 蓄积，这意味着儿茶素抑制了 P-糖蛋白（P-gp）外排泵的活性。与这些结果一致，细胞内同时用 DOX 和 ECG 或 EGCG 处理后，P-gp 底物罗丹明 123 的保留增加，P-gp 水平降低。EGCG 增加拓扑异构酶 II 的表达，但不改变肿瘤异种移植物中的 GST 蛋白水平。MDR1 和 HIF-1alpha mRNA 的表达明显降低，而 MRP1 和 LRP 的表达变化不明显。这些数据表明，在非毒性剂量下，茶儿茶素可以增强 DOX 诱导的细胞杀伤作用，并使耐药 HCC 细胞对 DOX 敏感。儿茶素的化疗增敏作用可能直接或间接发生，通过逆转多药耐药，涉及抑制 MDR1 表达，或通过增强细胞内 DOX 蓄积，涉及抑制 P-gp 功能。
