Dynamic vs static ABCG2 inhibitors to sensitize drug resistant cancer cells.
Dynamic vs static ABCG2 inhibitors to sensitize drug resistant cancer cells.
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动态与静态 ABCG2 抑制剂使耐药癌细胞变得敏感。
DOI：
10.1371/journal.pone.0015276
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发表时间：
2010-12-07
期刊：
影响因子：
3.7
通讯作者：
Zhang JT
中科院分区：
文献类型：
--
作者：
Peng H;Qi J;Dong Z;Zhang JT
人ABCG2是三磷酸腺苷结合盒转运子超家族的成员之一，在多药耐药和保护肿瘤干细胞方面发挥着关键作用。ABCG2基因敲除对小鼠的发育、生化和生命无明显不良影响。因此，ABCG2是开发化学增敏剂的有趣和有前途的靶点，以更好地治疗耐药癌症和消除癌症干细胞。此前，我们报道了一种新型的双模式作用ABCG2抑制剂PZ-39，它除了抑制ABCG2的活性外，还能诱导ABCG2的降解。在这篇手稿中，我们报道了我们在鉴定两组不同的ABCG2抑制剂方面的最新进展，一组只抑制ABCG2的功能(静态)，另一组除了抑制溶酶体的功能外，还能诱导ABCG2的降解(动态)。因此，抑制剂诱导的ABCG2降解可能比我们先前预期的更常见，进一步研究诱导ABCG2降解的动态抑制剂可能提供一种更有效的方法来增敏ABCG2介导的肿瘤化疗中的多药耐药。
Human ABCG2, a member of the ATP-binding cassette transporter superfamily, plays a key role in multidrug resistance and protecting cancer stem cells. ABCG2-knockout had no apparent adverse effect on the development, biochemistry, and life of mice. Thus, ABCG2 is an interesting and promising target for development of chemo-sensitizing agents for better treatment of drug resistant cancers and for eliminating cancer stem cells. Previously, we reported a novel two mode-acting ABCG2 inhibitor, PZ-39, that induces ABCG2 degradation in addition to inhibiting its activity. In this manuscript, we report our recent progresses in identifying two different groups of ABCG2 inhibitors with one inhibiting only ABCG2 function (static) and the other induces ABCG2 degradation in lysosome in addition to inhibiting its function (dynamic). Thus, the inhibitor-induced ABCG2 degradation may be more common than we previously anticipated and further investigation of the dynamic inhibitors that induce ABCG2 degradation may provide a more effective way of sensitizing ABCG2-mediated MDR in cancer chemotherapy.
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