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癌症的一个抗药性机制

摘要 : 加拿大蒙特利尔大学和麦吉尔大学的研究人员发现抗药性肿瘤细胞含有高水平的GLI1,GLI1的抑制能克服抗药性,从而为消除一些患者的抗药性提供一个潜在的策略。相关文章发表于2014年5月28日的《Nature》杂志上。

这项研究报告了对“急性骨髓性白血病”的治疗措施所产生的一种抗药性,这种形式的抗药性是以前人们不知道的,同时还识别出能够恢复抗药性细胞的药物敏感性的一种药物。

接受二期临床试验的患者,对用cytarabine (Ara-C)和一种较新的药物ribavirin所做的治疗反应良好,但随后对用这两种药物治疗便不再有反应。

Katherine Borden及同事发现,这两种药物会被葡糖醛酸化,从而失去活性。抗药性肿瘤细胞含有高水平的GLI1,它是在 Sonic hedgehog信号传导中所涉及的一个因子,专门增加负责药物修饰的UGT1A 酶的生成。GLI1的抑制能克服抗药性,从而为消除一些患者的抗药性提供一个潜在的策略。

原文摘要:

The sonic hedgehog factor GLI1 imparts drug resistance through inducible glucuronidation

Hiba Ahmad Zahreddine, Biljana Culjkovic-Kraljacic, Sarit Assouline, Patrick Gendron,Andrea A. Romeo, Stephen J. Morris, Gregory Cormack, James B. Jaquith, Leandro Cerchietti, Eftihia Cocolakis, Abdellatif Amri, Julie Bergeron, Brian Leber, Michael W. Becker, Shanshan Pei, Craig T. Jordan, Wilson H. Miller & Katherine L. B. Borden

Drug resistance is a major hurdle in oncology. Responses of acute myeloid leukaemia (AML) patients to cytarabine (Ara-C)-based therapies are often short lived with a median overall survival of months. Therapies are under development to improve outcomes and include targeting the eukaryotic translation initiation factor (eIF4E) with its inhibitor ribavirin. In a Phase II clinical trial in poor prognosis AML, ribavirin monotherapy yielded promising responses including remissions; however, all patients relapsed. Here we identify a novel form of drug resistance to ribavirin and Ara-C. We observe that the sonic hedgehog transcription factor glioma-associated protein 1 (GLI1) and the UDP glucuronosyltransferase (UGT1A) family of enzymes are elevated in resistant cells. UGT1As add glucuronic acid to many drugs, modifying their activity in diverse tissues. GLI1 alone is sufficient to drive UGT1A-dependent glucuronidation of ribavirin and Ara-C, and thus drug resistance. Resistance is overcome by genetic or pharmacological inhibition of GLI1, revealing a potential strategy to overcome drug resistance in some patients.

对应Nature杂志: 2014年7月3日Nature杂志精选

来源: Nature中文 浏览次数:113

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