双重Src激酶/ Pretubulin抑制剂KX-01,糖分会让ERalpha-negative乳腺癌三苯氧胺通过ERalpha Reexpression。
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Anbalagan米、盛米,弗莱舍B,张Y, Y,黄平君V, Matossian M,伯克斯他Burow我,Collins-Burow BM, Hangauer D,罗文BG
双重Src激酶/ Pretubulin抑制剂KX-01,糖分会让ERalpha-negative乳腺癌三苯氧胺通过ERalpha Reexpression。
摩尔癌症研究》2017年11月,15 (11):1491 - 1502。doi: 10.1158 / 1541 - 7786. - mcr - 16 - 0297 t。Epub 2017年7月27日。
- PubMed ID
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28751463 (在PubMed]
- 文摘
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与乳腺癌是雌激素阳性receptor-alpha (ERalpha),没有靶向治疗三阴乳腺癌(TNBC)。ERalpha沉默在TNBC通过表观遗传变化包括DNA甲基化和组蛋白乙酰化作用。恢复ERalpha TNBC表达可能使敏感患者内分泌治疗。c - src的表达在乳腺癌和ERalpha具有负相关性表明c - src抑制可能导致reexpression TNBC的ERalpha。KX-01是肽substrate-targeted Src / pretubulin实体肿瘤抑制剂在临床试验中。KX-01(1毫克/公斤的身体每天weight-twice)抑制增长tamoxifen-resistant mda - mb - 231和mda - mb - 157 TNBC异种移植于裸小鼠与Src激酶抑制相关。KX-01也增加了ERalpha信使rna和蛋白质,以及增加了ERalpha目标孕激素受体(PR), pS2 (TFF1),细胞周期蛋白D1 (CCND1)和原癌基因(MYC) mda - mb - 231和mda - mb - 468,但不是mda - mb - 157异种移植。mda - mb - 231和mda - mb - 468肿瘤表现出减少间质标记(波形蛋白,β-连环蛋白)和增加上皮标记(上皮)暗示mesenchymal-to-epithelial过渡(满足)。KX-01敏化mda - mb - 231和mda - mb - 468肿瘤它莫西芬生长抑制和它莫西芬ERalpha目标pS2的镇压,细胞周期蛋白D1和原癌基因。染色质免疫沉淀反应(芯片)ERalpha发起人KX-01-treated肿瘤证明浓缩的活跃转录标记(acetyl-H3 acetyl-H3Lys9) HDAC1离解,RNA聚合酶II的招聘。 Methylation-specific PCR and bisulfite sequencing demonstrated no alteration in ERalpha promoter methylation by KX-01. These data demonstrate that in addition to Src kinase inhibition, peptidomimetic KX-01 restores ERalpha expression in TNBC through changes in histone acetylation that sensitize tumors to tamoxifen.Implications: Src kinase/pretubulin inhibitor KX-01 restores functional ERalpha expression in ERalpha(-) breast tumors, a novel treatment strategy to treat triple-negative breast cancer. Mol Cancer Res; 15(11); 1491-502. (c)2017 AACR.
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