Hedgehog pathway inhibitor HhAntag691 is a potent inhibitor of ABCG2/BCRP and ABCB1/Pgp.
Hedgehog pathway inhibitor HhAntag691 is a potent inhibitor of ABCG2/BCRP and ABCB1/Pgp.
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DOI：
10.1593/neo.81264
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发表时间：
2009
期刊：
影响因子：
4.8
通讯作者：
Yimao Zhang;J. Laterra;M. Pomper
中科院分区：
文献类型：
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作者：
Yimao Zhang;J. Laterra;M. Pomper
HhAntag 691（GDC-0449）是一种促肿瘤刺猬（Hh）信号通路的低分子量抑制剂，已用于治疗动物模型中的髓母细胞瘤，最近已进入各种实体瘤的临床试验。在这里，我们表明，HhAntag 691抑制多种ATP结合盒（ABC）转运。ATP结合盒转运蛋白属于膜蛋白家族，其过表达与多药耐药性相关，这是成功治疗癌症的主要障碍。HhAntag 691是两种ABC转运蛋白ABCG 2/BCRP和ABCB 1/Pgp的强效抑制剂，也是ABCC 1/MRP 1的轻度抑制剂。在ABCG 2过表达的HEK 293细胞中，HhAntag 691增加了荧光ABCG 2底物BODIPY-哌唑嗪的保留，并使这些细胞对ABCG 2底物米托蒽醌重新敏感。在Madin-Darby犬肾II细胞工程过表达Pgp或MRP 1，HhAntag 691增加了钙黄绿素-AM的保留，并使它们对秋水仙碱重新敏感。HhAntag 691还使人非小细胞肺癌细胞NCI-H460/par和NCI-H460/MX20再敏感，其响应于米托蒽醌、米托蒽醌和托泊替康或SN-38而过表达ABCG 2。HhAntag 691抑制ABCG 2和Pgp的IC（50）值分别约为1.4和3.0 μ M。由于ABC转运蛋白在血脑屏障和许多肿瘤细胞上高度表达，因此它们显著导致许多类型的癌症，特别是神经轴内的癌症的治疗失败。除了其对Hh信号传导的作用外，HhAntag 691和相关化合物抑制两种关键ABC转运蛋白的能力可能有助于其治疗恶性肿瘤的有效性。
HhAntag691 (GDC-0449), a low-molecular weight inhibitor of the tumor-promoting hedgehog (Hh) signaling pathway, has been used to treat medulloblastoma in animal models and has recently entered clinical trials for a variety of solid tumors. Here, we show that HhAntag691 inhibits multiple ATP-binding cassette (ABC) transporters. ATP-binding cassette transporters are within a family of membrane proteins, the overexpression of which is associated with multidrug resistance, a major impediment to successful cancer treatment. HhAntag691 is a potent inhibitor of two ABC transporters, ABCG2/BCRP and ABCB1/Pgp, and is a mild inhibitor of ABCC1/MRP1. In ABCG2-overexpressing HEK293 cells, HhAntag691 increased retention of the fluorescent ABCG2 substrate BODIPY-prazosin and resensitized these cells to mitoxantrone, an antineoplastic ABCG2 substrate. In Madin-Darby canine kidney II cells engineered to overexpress Pgp or MRP1, HhAntag691 increased the retention of calcein-AM and resensitized them to colchicine. HhAntag691 also resensitized human non-small cell lung carcinoma cells NCI-H460/par and NCI-H460/MX20, which overexpress ABCG2 in response to mitoxantrone, to mitoxantrone, and to topotecan or SN-38. The IC(50) values of HhAntag691 for inhibition of ABCG2 and Pgp were approximately 1.4 and approximately 3.0 microM, respectively. Because ABC transporters are highly expressed at the blood-brain barrier and on many tumor cells, they contribute significantly to treatment failure of many types of cancer, particularly of those within the neuraxis. In addition to its effect on Hh signaling, the ability of HhAntag691 and related compounds to inhibit two key ABC transporters could contribute to their effectiveness in treating malignancies.