通过抑制药物外排泵 MRP3 使胆管癌对化疗敏感。

Sensitizing cholangiocarcinoma to chemotherapy by inhibition of the drug-export pump MRP3.

机构信息

Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, Salamanca, Spain; Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Carlos III National Institute of Health, Madrid, Spain.

Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, Salamanca, Spain.

出版信息

Biomed Pharmacother. 2024 Nov;180:117533. doi: 10.1016/j.biopha.2024.117533. Epub 2024 Oct 13.

DOI:10.1016/j.biopha.2024.117533

PMID:39405909

Abstract

AIMS

Drug export through ABC proteins hinders cancer response to chemotherapy. Here, we have evaluated the relevance of MRP3 (ABCC3) in cholangiocarcinoma (CCA) as a potential target to overcome drug resistance.

METHODS

Gene expression was analyzed in silico using the TCGA-CHOL database and experimentally (mRNA and protein) in resected CCA tumors. The effect of manipulating MRP3 function/expression was evaluated in vitro and in vivo.

RESULTS

High MRP3 expression at the plasma membrane of human CCA cells was found. MRP3 overexpression in HEK293T cells selectively impaired the cytotoxic effect of etoposide, cisplatin, SN-38, and mitoxantrone. Reduced MRP3 activity with shRNAs or pan-MRP blockers enhanced the sensitivity to these drugs. MRP3 interaction with natural and semisynthetic compounds (≈40,000) was evaluated by virtual drug screening and molecular docking. Two identified potential MRP3 inhibitors (EM-114, EM-188), and sorafenib impaired MRP3 transport activity and enhanced sensitivity of CCA cells to etoposide and cisplatin. The antitumor effect of cisplatin in the mouse xenograft model was enhanced by co-treatment with sorafenib, which was accompanied by a higher intratumor accumulation of cisplatin.

CONCLUSIONS

Genetic and pharmacological MRP3 inhibition enhances the anti-CCA effect of several drugs, which constitutes a promising strategy to improve the response to chemotherapy in CCA patients.

摘要

目的

ABC 蛋白介导的药物外排会阻碍癌症对化疗的反应。在此，我们评估了多药耐药相关蛋白 3（MRP3，ABCC3）在胆管癌（CCA）中的相关性，将其作为克服耐药性的潜在靶点。

方法

使用 TCGA-CHOL 数据库进行基于计算机的基因表达分析，并在切除的 CCA 肿瘤中进行实验（mRNA 和蛋白质）分析。体外和体内评估了操纵 MRP3 功能/表达的效果。

结果

在人类 CCA 细胞的质膜上发现了高表达的 MRP3。MRP3 在 HEK293T 细胞中的过表达选择性地损害了依托泊苷、顺铂、SN-38 和米托蒽醌的细胞毒性作用。用 shRNAs 或泛 MRP 阻滞剂降低 MRP3 活性增强了对这些药物的敏感性。通过虚拟药物筛选和分子对接评估了 MRP3 与天然和半合成化合物（约 40000 种）的相互作用。通过虚拟药物筛选和分子对接鉴定了两种潜在的 MRP3 抑制剂（EM-114、EM-188）和索拉非尼，它们可损害 MRP3 转运活性并增强 CCA 细胞对依托泊苷和顺铂的敏感性。索拉非尼与顺铂联合治疗增强了顺铂在小鼠异种移植模型中的抗肿瘤作用，同时伴随着顺铂在肿瘤内的更高积累。