Jekerle Veronika, Klinkhammer Werner, Reilly Raymond M, Piquette-Miller Micheline, Wiese Michael
Pharmaceutical Institute, University of Bonn, Bonn, Germany.
Cancer Chemother Pharmacol. 2007 Jan;59(1):61-9. doi: 10.1007/s00280-006-0244-3. Epub 2006 Apr 25.
The ATP-binding cassette transporters P-glycoprotein (Pgp) and BCRP are implicated in multidrug resistance (MDR) of many tumors. Multi-targeted inhibitors such as cyclosporin A, have been shown to circumvent MDR in clinical trials. Here, we present the characterization of a novel class of effective and multi-targeted tetrahydroisoquinolin-ethyl-phenylamine based MDR inhibitors.
The novel MDR inhibitors, XR9577, WK-X-34, WK-X-50 and WK-X-84 were examined for cellular toxicity in several cell lines. Chemosensitivity and inhibition of BCRP-mediated mitoxantrone efflux were analyzed in BCRP-overexpressing MCF7/mx cells. Chemosensitivity towards daunorubicin and inhibition of Pgp-mediated efflux of (99m)Tc-Sestamibi were examined in Pgp-overexpressing A2780/Adr cells. Potential MRP-interactions were evaluated with 5-CFDA efflux assays in selectively transfected MRP-1, -2 and -3 cell lines.
All WK-X-compounds showed significant BCRP inhibition in the MCF7/mx cells resulting in significant increases in mitoxantrone intracellular accumulation and 200-300 fold increases in mitroxantrone cytotoxicity. WK-X-34 and XR9577 were also potent inhibitors of Pgp, increasing (99m)Tc-Sestamibi accumulation with IC(50) values in the nM range. Daunorubicin cytotoxicity was also increased seven to eight-fold in cells co-treated with XR9577 or WK-X-34 (10 muM). These compounds did not appear to interact with the MRP transporters. As compared to cyclosporin A, these compounds showed reduced cellular toxicity and increased potency of BCRP and Pgp inhibition.
The novel MDR inhibitors WK-X-34 and XR9577 demonstrate superior effectiveness in Pgp and BCRP inhibition, in vitro tolerance and specificity over cyclosporin A. The novel compounds might be the promising candidates for a broad-spectrum based approach to the circumvention of MDR in resistant tumors.
ATP结合盒转运蛋白P-糖蛋白（Pgp）和乳腺癌耐药蛋白（BCRP）与多种肿瘤的多药耐药性（MDR）有关。多靶点抑制剂如环孢素A在临床试验中已被证明可克服MDR。在此，我们介绍一类新型的基于四氢异喹啉-乙基-苯胺的有效多靶点MDR抑制剂的特性。
检测新型MDR抑制剂XR9577、WK-X-34、WK-X-50和WK-X-84在几种细胞系中的细胞毒性。在过表达BCRP的MCF7/mx细胞中分析化学敏感性以及对BCRP介导的米托蒽醌外排的抑制作用。在过表达Pgp的A2780/Adr细胞中检测对柔红霉素的化学敏感性以及对Pgp介导的（99m）Tc-司他米比外排的抑制作用。在选择性转染MRP-1、-2和-3的细胞系中用5-羧基荧光素二乙酸酯（5-CFDA）外排试验评估潜在的多药耐药相关蛋白（MRP）相互作用。
所有WK-X化合物在MCF7/mx细胞中均显示出显著的BCRP抑制作用，导致米托蒽醌细胞内蓄积显著增加，米托蒽醌细胞毒性增加200 - 300倍。WK-X-34和XR9577也是Pgp的有效抑制剂，使（99m）Tc-司他米比蓄积增加，IC（50）值在纳摩尔范围内。在用XR9577或WK-X-34（10 μM）共同处理的细胞中，柔红霉素细胞毒性也增加了7至8倍。这些化合物似乎不与MRP转运蛋白相互作用。与环孢素A相比，这些化合物显示出更低的细胞毒性以及更强的BCRP和Pgp抑制效力。
新型MDR抑制剂WK-X-34和XR9577在抑制Pgp和BCRP方面、体外耐受性和特异性方面均优于环孢素A。这些新型化合物可能是基于广谱方法克服耐药肿瘤中MDR的有前景的候选药物。
