Plos One, 2015, 10(3).

Regulation of Multidrug Resistance Proteins by Genistein in a Hepatocarcinoma Cell Line: Impact on Sorafenib Cytotoxicity

Juan Pablo Rigalli, Nadia Ciriaci, Agostina Arias, et al

Institute of Experimental Physiology (IFISE-CONICET), Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina; Institute of Pharmacological Investigations (ININFA-CONICET), Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina

Hepatocellular carcinoma (HCC) is the fifth most frequent cancer worldwide. Sorafenib is the only drug available that improves the overall survival of HCC patients. P-glycoprotein (P-gp), Multidrug resistance-associated proteins 2 and 3 (MRP2 and 3) and Breast cancer resistance protein (BCRP) are efflux pumps that play a key role in cancer chemoresistance. Their modulation by dietary compounds may affect the intracellular accumulation and therapeutic efficacy of drugs that are substrates of these transporters. Genistein (GNT) is a phytoestrogen abundant in soybean that exerts its genomic effects through Estrogen-Receptors and Pregnane-X-Receptor (PXR), which are involved in the regulation of the above-mentioned transporters. We evaluated the effect of GNT on the expression and activity of P-gp, MRP2, MRP3 and BCRP in HCC-derived HepG2 cells. GNT (at 1.0 and 10 μM) increased P-gp and MRP2 protein expression and activity, correlating well with an increased resistance to sorafenib cytotoxicity as detected by the methylthiazole tetrazolium (MTT) assay. GNT induced P-gp and MRP2 mRNA expression at 10 but not at 1.0 μM concentration suggesting a different pattern of regulation depending on the concentration. Induction of both transporters by 1.0 μM GNT was prevented by cycloheximide, suggesting translational regulation. Downregulation of expression of the miR-379 by GNT could be associated with translational regulation of MRP2. Silencing of PXR abolished P-gp induction by GNT (at 1.0 and 10 μM) and MRP2 induction by GNT (only at 10 μM), suggesting partial mediation of GNT effects by PXR. Taken together, the data suggest the possibility of nutrient-drug interactions leading to enhanced chemoresistance in HCC when GNT is ingested with soy rich diets or dietary supplements.

美国《公共科学图书馆》, 2015, 10(3).

在肝癌细胞中金雀异黄素对抗多药蛋白的调节︰ 对索拉非尼细胞毒性的影响
乔安 帕波楼 芮盖丽，纳蒂亚 科瑞埃克，等
罗萨里奥国立大学生物化学和药物科学学院实验生理学研究所（IFISE-CONICET），罗萨里奥，阿根廷; 阿根廷布宜诺斯艾利斯布宜诺斯艾利斯大学药理学研究所（ININFA-CONICET），药学与生物化学系

肝细胞癌（HCC）是全球第五大癌症。索拉菲尼是唯一可用于改善HCC患者总体生存的药物。 P-糖蛋白（P-gp），多药耐药相关蛋白2和3（MRP2和3）和乳腺癌耐药蛋白（BCRP）是外排泵，在癌症化学耐药中起关键作用。它们通过膳食化合物的调节可能影响作为这些转运蛋白底物的药物的细胞内积累和治疗功效。染料木黄酮（GNT）是大豆中丰富的植物雌激素，通过参与上述转运蛋白调节的雌激素受体和孕激素受体（PXR）发挥其基因组作用。我们评估了GNT对HCC衍生的HepG2细胞中P-gp，MRP2，MRP3和BCRP的表达和活性的影响。 GNT（1.0和10μM）增加P-gp和MRP2蛋白表达和活性，与通过甲基噻唑四唑（MTT）测定检测到的对索拉非尼细胞毒性的增加的抗性相关。 GNT在10处诱导P-gp和MRP2 mRNA表达，但不是在1.0μM浓度，表明根据浓度的不同调节模式。通过放线菌酮防止1.0μMGNT对两种转运蛋白的诱导，提示翻译调控。由GNT下调miR-379的表达可能与MRP2的翻译调节有关。 PXR的沉默消除了GNT（1.0和10μM）和GNT（仅在10μM）诱导的MRP2的P-gp诱导，表明PXR对GNT作用的部分调节。总之，数据表明营养 - 药物相互作用的可能性导致当GNT被大豆丰富的饮食或膳食补充剂摄入时，HCC中的化学耐药性增强。