Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
PLoS One. 2010 Dec 7;5(12):e15276. doi: 10.1371/journal.pone.0015276.
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.
人 ABCG2，ATP 结合盒转运体超家族的成员，在多药耐药和保护肿瘤干细胞中发挥关键作用。ABCG2 敲除对小鼠的发育、生化和生活没有明显的不良影响。因此，ABCG2 是开发化学增敏剂的一个有趣且有前途的靶点，可更好地治疗耐药性癌症并消除肿瘤干细胞。此前，我们报道了一种新型的双模式作用 ABCG2 抑制剂 PZ-39，它除了抑制其活性外，还诱导 ABCG2 降解。在本文中，我们报告了我们在鉴定两种不同类型的 ABCG2 抑制剂方面的最新进展，一种抑制剂仅抑制 ABCG2 功能（静态），另一种抑制剂除了抑制其功能外，还在溶酶体中诱导 ABCG2 降解（动态）。因此，抑制剂诱导的 ABCG2 降解可能比我们之前预期的更为常见，进一步研究诱导 ABCG2 降解的动态抑制剂可能为癌症化疗中增强 ABCG2 介导的多药耐药性提供更有效的方法。
