Yakult Central Institute for Microbiological Research, Yakult Honsha Co., Ltd., 1796 Yaho, Kunitachi-shi, Tokyo, 186-8650 Japan.
Mol Cancer Ther. 2011 Jul;10(7):1252-63. doi: 10.1158/1535-7163.MCT-10-0874. Epub 2011 May 12.
Breast cancer resistance protein (BCRP/ABCG2) confers resistance to anticancer drugs such as 7-ethyl-10-hydroxycamptothecin (SN-38, an active metabolite of irinotecan), mitoxantrone, and topotecan. In this study, we examined the reversing effects of YHO-13177, a novel acrylonitrile derivative, and its water-soluble diethylaminoacetate prodrug YHO-13351 on the BCRP-mediated drug resistance. YHO-13177 potentiated the cytotoxicity of SN-38, mitoxantrone, and topotecan in both BCRP-transduced human colon cancer HCT116 (HCT116/BCRP) cells and SN-38-resistant human lung cancer A549 (A549/SN4) cells that express BCRP, but had little effect in the parental cells. In addition, YHO-13177 potentiated the cytotoxicity of SN-38 in human lung cancer NCI-H460 and NCI-H23, myeloma RPMI-8226, and pancreatic cancer AsPC-1 cells that intrinsically expressed BCRP. In contrast, it had no effect on P-glycoprotein-mediated paclitaxel resistance in MDR1-transduced human leukemia K562 cells and multidrug resistance-related protein 1-mediated doxorubicin resistance in MRP1-transfected human epidermoid cancer KB-3-1 cells. YHO-13177 increased the intracellular accumulation of Hoechst 33342, a substrate of BCRP, at 30 minutes and partially suppressed the expression of BCRP protein at more than 24 hours after its treatment in both HCT116/BCRP and A549/SN4 cells. In mice, YHO-13351 was rapidly converted into YHO-13177 after its oral or intravenous administration. Coadministration of irinotecan with YHO-13351 significantly increased the survival time of mice inoculated with BCRP-transduced murine leukemia P388 cells and suppressed the tumor growth in an HCT116/BCRP xenograft model, whereas irinotecan alone had little effect in these tumor models. These findings suggest that YHO-13351, a prodrug of YHO-13177, could be clinically useful for reversing BCRP-mediated drug resistance in cancer chemotherapy.
乳腺癌耐药蛋白（BCRP/ABCG2）使癌细胞对多种抗癌药物产生耐药性，如 7-乙基-10-羟基喜树碱（伊立替康的活性代谢物 SN-38）、米托蒽醌和拓扑替康。在这项研究中，我们研究了一种新型丙烯腈衍生物 YHO-13177 及其水溶性二乙氨基乙酸酯前药 YHO-13351 对 BCRP 介导的耐药性的逆转作用。YHO-13177 增强了 SN-38、米托蒽醌和拓扑替康在转染 BCRP 的人结肠癌细胞 HCT116（HCT116/BCRP）和 SN-38 耐药的人肺癌 A549（A549/SN4）细胞中的细胞毒性，但对亲本细胞几乎没有影响。此外，YHO-13177 增强了内在表达 BCRP 的人肺癌 NCI-H460 和 NCI-H23、骨髓瘤 RPMI-8226 和胰腺癌 AsPC-1 细胞中 SN-38 的细胞毒性。相比之下，它对转染 P-糖蛋白的人白血病 K562 细胞中紫杉醇耐药和转染多药耐药相关蛋白 1 的人表皮样癌细胞 KB-3-1 中阿霉素耐药没有影响。YHO-13177 在 30 分钟内增加了 BCRP 底物 Hoechst 33342 的细胞内积累，并在处理后 24 小时以上部分抑制了 HCT116/BCRP 和 A549/SN4 细胞中 BCRP 蛋白的表达。在小鼠中，YHO-13351 口服或静脉给药后迅速转化为 YHO-13177。伊立替康与 YHO-13351 联合应用显著延长了转染 BCRP 的小鼠白血病 P388 细胞接种小鼠的存活时间，并抑制了 HCT116/BCRP 异种移植模型中的肿瘤生长，而伊立替康单独在这些肿瘤模型中几乎没有作用。这些发现表明，YHO-13351（YHO-13177 的前体药物）可能在癌症化疗中逆转 BCRP 介导的耐药性方面具有临床应用价值。
