Backstabbing P-gp: Side-Chain Cleaved Ecdysteroid 2,3-Dioxolanes Hyper-Sensitize MDR Cancer Cells to Doxorubicin without Efflux Inhibition

A. Hunyadi, J. Csábi, A. Martins, J. Molnár, Attila Balázs, G. Tóth
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引用次数: 27

Abstract

P-glycoprotein (P-gp, ABCB1) over-expression, causing a multi-drug resistant (MDR) phenotype, is a major problem in cancer chemotherapy that urgently requires novel approaches. Our previous studies showed certain ecdysteroid derivatives as promising chemo-sensitizers against MDR and non-MDR cancer cell lines while also exerting mild to moderate inhibition of P-gp function. Here we report the preparation of a set of substituted 2,3-dioxolane derivatives of poststerone, a known in vivo metabolite of 20-hydroxyecdysone (20E). In contrast with previously studied ecdysteroid dioxolanes, the majority of the new compounds did not inhibit the efflux function of P-gp. Nevertheless, a strong, dose dependent sensitization to doxorubicin was observed on a P-gp transfected cancer cell line and on its susceptible counterpart. We also observed that the MDR cell line was more sensitive to the compounds’ effect than the non-MDR. Our results showed for the first time that the chemo-sensitizing activity of ecdysteroids can be fully independent of functional efflux pump inhibition, and suggest these compounds as favorable leads against MDR cancer.
背刺P-gp:侧链切割的表皮甾体2,3-二恶氧烷使耐多药癌细胞对阿霉素高度敏感而无外排抑制
p -糖蛋白(P-gp, ABCB1)过表达导致多药耐药(MDR)表型是癌症化疗中的一个主要问题,迫切需要新的治疗方法。我们之前的研究表明,某些表皮甾体衍生物作为耐多药和非耐多药癌细胞系的有希望的化学增敏剂,同时也对P-gp功能有轻度至中度的抑制作用。在这里,我们报道了一组取代的2,3-二恶烷后酮衍生物的制备,后酮是一种已知的20-羟基蜕皮酮(20E)的体内代谢物。与先前研究的外甾类二氧唑烷相比,大多数新化合物不抑制P-gp的外排功能。然而,在P-gp转染的癌细胞系及其易感细胞系上观察到对阿霉素的强剂量依赖性敏化。我们还观察到耐多药细胞系对化合物的作用比非耐多药细胞系更敏感。我们的研究结果首次表明,体外类固醇的化学增敏活性可以完全独立于功能性外排泵抑制,并表明这些化合物是抗耐多药癌症的有利先导。
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