Ethyl 2-Amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (CXL017): A Novel Scaffold That Resensitizes Multidrug Resistant Leukemia Cells to Chemotherapy
Ethyl 2-Amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (CXL017): A Novel Scaffold That Resensitizes Multidrug Resistant Leukemia Cells to Chemotherapy
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DOI：
10.1021/cb300460f
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发表时间：
2013-02-01
影响因子：
4
通讯作者：
Xing, Chengguo
中科院分区：
文献类型：
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作者：
Das, Sonia G.;Hermanson, David L.;Xing, Chengguo
多药耐药性（MDR）是癌症治疗的主要障碍，迫切需要新的疗法。我们最近开发了 2-氨基-6-(3,5-二甲氧基苯基)-4-(2-乙氧基-2-氧代乙基)-4H-色烯-3-羧酸乙酯 (CXL017)，源自 Bcl-2 和 SERCA 蛋白的双重抑制剂 sHA 14-1，在体外对 MDR 癌细胞系具有选择性细胞毒性。在这项研究中，我们提供了新的证据来证明其在治疗耐多药癌症方面的治疗潜力，并为其优先靶向耐药癌症提供了机制见解。 CXL017 在体内选择性抑制来自 MDR 癌细胞系 HL60/MX2 的肿瘤生长。此外，即使长期暴露于CXL017后，HL60/MX2也未能对CXL017产生稳定的耐药性，而对阿糖胞苷（Ara-C）（治疗急性髓系白血病（AML）的主要一线化疗药物）获得了>2000倍的耐药性。值得注意的是，接触 CXL017 的 HL60/MX2 细胞并没有获得进一步的交叉耐药性，而是对标准疗法重新敏感（10 至 100 倍）。蛋白质印迹分析显示，CXL017 暴露显着下调 Mcl-1 和 Bax，上调 Noxa、Bim、Bcl-X-L、SERCA2 和 SERCA3 蛋白，同时内质网 (ER) 钙含量降低。鉴于 Bcl-2 家族蛋白和 ER 钙在耐药性中的明确功能，我们的结果表明，Mcl-1 的下调和 Noxa 和 Bim 的上调以及 ER 钙含量的降低可能是 CXL017 诱导 MDR 癌细胞重新敏化的原因。这些数据还证明了 CXL017 在癌症治疗中克服 MDR 的独特潜力。
Multidrug resistance (MDR) is a major hurdle in the treatment of cancer, and there is a pressing need for new therapies. We have recently developed ethyl 2-amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (CXL017), derived from a dual inhibitor of Bcl-2 and SERCA proteins, sHA 14-1, with selective cytotoxicity toward MDR cancer cell lines in vitro. In this study, we present new evidence for its therapeutic potential in treatment of MDR cancers and offer mechanistic insights toward its preferential targeting of drug-resistant cancer. CXL017 selectively suppressed the growth of tumors derived from the MDR cancer cell line, HL60/MX2, in vivo. In addition, even after chronic exposure to CXL017, HL60/MX2 failed to develop stable resistance to CXL017, whereas it acquired >2000-fold resistance to cytarabine (Ara-C), the major first-line chemotherapy for the treatment of acute myeloid leukemia (AML). Remarkably, instead of acquiring further cross-resistance, HL60/MX2 cells exposed to CXL017 were resensitized to standard therapies (10- to 100-fold). Western blotting analyses revealed that CXL017 exposure significantly downregulated Mcl-1 and Bax and up-regulated Noxa, Bim, Bcl-X-L, SERCA2, and SERCA3 proteins, along with a reduction in endoplasmic reticulum (ER) calcium content. Given the well-established functions of Bcl-2 family proteins and ER calcium in drug resistance, our results suggest that the down-regulation of Mcl-1 and the up-regulation of Noxa and Bim along with the decrease in ER calcium content are likely responsible for CXL017-induced resensitization of MDR cancer cells. These data also demonstrate the unique potential of CXL017 to overcome MDR in cancer treatment.