代谢糖工程使耐药胰腺癌细胞对酪氨酸激酶抑制剂厄洛替尼和吉非替尼敏感。
Metabolic glycoengineering sensitizes drug-resistant pancreatic cancer cells to tyrosine kinase inhibitors erlotinib and gefitinib.
作者信息
Mathew Mohit P, Tan Elaine, Saeui Christopher T, Bovonratwet Patawut, Liu Lingshu, Bhattacharya Rahul, Yarema Kevin J
机构信息
Department of Biomedical Engineering and the Translational Tissue Engineering Center, The Johns Hopkins University, 5029 Robert H. & Clarice Smith Building, 400 North Broadway, Baltimore, MD 21231, USA.
Department of Biomedical Engineering and the Translational Tissue Engineering Center, The Johns Hopkins University, 5029 Robert H. & Clarice Smith Building, 400 North Broadway, Baltimore, MD 21231, USA.
出版信息
Bioorg Med Chem Lett. 2015 Mar 15;25(6):1223-7. doi: 10.1016/j.bmcl.2015.01.060. Epub 2015 Feb 4.
Metastatic human pancreatic cancer cells (the SW1990 line) that are resistant to the EGFR-targeting tyrosine kinase inhibitor drugs (TKI) erlotinib and gefitinib were treated with 1,3,4-O-Bu3ManNAc, a 'metabolic glycoengineering' drug candidate that increased sialylation by ∼2-fold. Consistent with genetic methods previously used to increase EGFR sialylation, this small molecule reduced EGF binding, EGFR transphosphorylation, and downstream STAT activation. Significantly, co-treatment with both the sugar pharmacophore and the existing TKI drugs resulted in strong synergy, in essence re-sensitizing the SW1990 cells to these drugs. Finally, 1,3,4-O-Bu3ManNAz, which is the azido-modified counterpart to 1,3,4-O-Bu3ManNAc, provided a similar benefit thereby establishing a broad-based foundation to extend a 'metabolic glycoengineering' approach to clinical applications.
对表皮生长因子受体（EGFR）靶向酪氨酸激酶抑制剂药物（TKI）厄洛替尼和吉非替尼耐药的转移性人胰腺癌细胞（SW1990细胞系），用1,3,4-O-三丁基- N-乙酰神经氨酸（1,3,4-O-Bu3ManNAc）进行处理，这是一种“代谢性糖工程”候选药物，可使唾液酸化增加约2倍。与先前用于增加EGFR唾液酸化的基因方法一致，这种小分子减少了表皮生长因子（EGF）结合、EGFR转磷酸化以及下游信号转导和转录激活因子（STAT）激活。重要的是，糖药效基团与现有TKI药物联合治疗产生了强大的协同作用，实质上使SW1990细胞对这些药物重新敏感。最后，1,3,4-O-三丁基- N-叠氮乙酰神经氨酸（1,3,4-O-Bu3ManNAz）是1,3,4-O-Bu3ManNAc的叠氮修饰类似物，也有类似效果，从而为将“代谢性糖工程”方法扩展到临床应用奠定了广泛基础。
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