白藜芦醇介导的癌细胞凋亡，以及多药耐药蛋白和代谢酶的调节。
Resveratrol mediated cancer cell apoptosis, and modulation of multidrug resistance proteins and metabolic enzymes.
机构信息
Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia; Department of Biochemistry, Faculty of Pharmacy, Al-Azhar University, 71524, Assiut, Egypt; Department of Pharmaceutical Biology, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, 69120, Heidelberg, Germany.
Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia; Department of Pharmaceutical Biology, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, 69120, Heidelberg, Germany.
出版信息
Phytomedicine. 2019 Mar 1;55:269-281. doi: 10.1016/j.phymed.2018.06.046. Epub 2018 Jun 28.
BACKGROUND
The degree of intracellular drug accumulation by specific membrane transporters, i.e., MDR1, BCRP, and MRP, and the degree of detoxification by intracellular metabolic enzymes, i.e., CYP3A4 and GST, provide control for cancer chemotherapy through diminishing the propensity of cancer cells to undergo apoptosis which in turn modulates the unresolved and complex phenomenon of multidrug resistance (MDR) for the cancer cells.
HYPOTHESIS/PURPOSE: This study dwells into the interaction details involving ABC-transporters, CYP3A4, GST and cytotoxic effects of resveratrol on different cell lines.
METHODS
Resveratrol was evaluated for its ability modulating the expression and efflux functions of P-gp /MDR1, MRP1, and BCRP in the multidrug-resistant human colon carcinoma cell line, Caco-2, and CEM/ADR5000 cells through flow cytometry and RTPCR technique.
RESULTS
The resveratrol influenced P-gp and MRP1 efflux functions whereby it increased rhodamine 123 with calcein accumulation in concentration-dependent manner (1 - 500 µM) in the Caco-2 cell lines and inhibited the effluxes of both the substrates also as concentration-dependent phenomenon (10 - 100 µM) in the p-gp overexpressing CEM/ADR5000 cells through FACS (full form). The treatment of drug-resistant Caco-2, and CEM/ADR5000 cells with doxorubicin (DOX) along with 20 µM of resveratrol in the mixture. It increased the cell sensitivity DOX towards the DOX and enhanced the cytotoxicity. The resveratrol inhibited both CYP3A4 and GST enzymatic activity in a concentration-dependent way and induced apoptosis in the resistance cell lines because of increased levels of caspase-3, -8,-6/9 and incremental phosphatidyl serine (PS) exposure as detected by flow cytometry. The treatment of Caco-2 cells with resveratrol showed significantly lower p-gp, MRP1, BCRP, CYP3A4, GST, and hPXR mRNA levels in a 48 h observation.
CONCLUSION
The result confirmed resveratrol mediated inhibition of ABC-transporters' overall efflux functions, and its expression, and apoptosis as well as metabolic enzymes GST and CYP3A4 activity.
背景
特定膜转运蛋白（即 MDR1、BCRP 和 MRP）的细胞内药物积累程度，以及细胞内代谢酶（即 CYP3A4 和 GST）的解毒程度，通过减少癌细胞发生凋亡的倾向，为癌症化疗提供了控制，而凋亡的倾向又调节了癌细胞多药耐药（MDR）这一未解决且复杂的现象。
假设/目的：本研究深入探讨了 ABC 转运蛋白、CYP3A4、GST 与白藜芦醇对不同细胞系细胞毒性作用的相互作用细节。
方法
通过流式细胞术和 RT-PCR 技术，评估白藜芦醇对多药耐药人结肠癌细胞系 Caco-2 和 CEM/ADR5000 细胞中 P-糖蛋白/MDR1、MRP1 和 BCRP 表达和外排功能的调节作用。
结果
白藜芦醇影响 P-糖蛋白和 MRP1 的外排功能，以浓度依赖的方式增加罗丹明 123 和 calcein 在 Caco-2 细胞系中的积累（1-500 μM），并抑制两种底物的外排，同样表现为浓度依赖性现象（10-100 μM）在 p-糖蛋白过度表达的 CEM/ADR5000 细胞中通过 FACS（全称）。用阿霉素（DOX）和 20 μM 白藜芦醇混合物处理耐药 Caco-2 和 CEM/ADR5000 细胞，增加了细胞对 DOX 的敏感性，并增强了细胞毒性。白藜芦醇以浓度依赖的方式抑制 CYP3A4 和 GST 酶活性，并通过流式细胞术检测到 caspase-3、-8、-6/9 和递增的磷脂酰丝氨酸（PS）暴露，诱导耐药细胞系凋亡。在 48 小时的观察中，用白藜芦醇处理 Caco-2 细胞，可显著降低 p-糖蛋白、MRP1、BCRP、CYP3A4、GST 和 hPXR mRNA 水平。
结论
结果证实白藜芦醇介导的 ABC 转运蛋白总体外排功能及其表达、凋亡以及代谢酶 GST 和 CYP3A4 活性的抑制。
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