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三(二亚苄基丙酮)二钯克服了多发性骨髓瘤中缺氧介导的耐药性。

Tris DBA palladium overcomes hypoxia-mediated drug resistance in multiple myeloma.

作者信息

de la Puente Pilar, Azab Feda, Muz Barbara, Luderer Micah, Arbiser Jack, Azab Abdel Kareem

机构信息

a Department of Radiation Oncology , Cancer Biology Division, Washington University in Saint Louis School of Medicine , St. Louis , MO , USA.

b Department of Dermatology , Emory University School of Medicine , Atlanta , GA , USA.

出版信息

Leuk Lymphoma. 2016 Jul;57(7):1677-86. doi: 10.3109/10428194.2015.1099645. Epub 2015 Nov 16.

Abstract

Despite recent progress in novel and targeted therapies, multiple myeloma (MM) remains a therapeutically challenging incurable disease. The regulation of important cellular processes and its link to cancer presented Src as an attractive target for MM. We suggest a novel strategy to improve the treatment of MM and overcome the drug resistance for the current therapeutic agents by specific inhibition of Src in MM cells by Tris (Dibenzylideneacetone) dipalladium (Tris DBA). Tris DBA reduces proliferation, induces G1 arrest and apoptosis in MM cells. Tris DBA showed additive effect with proteasome inhibitors reducing proliferation, cell cycle signaling, and increasing apoptosis more than each drug alone. Tris DBA overcame hypoxia-induced effects such as enhanced chemotaxis or drug resistance to proteasome inhibitors by inhibition of HIF1α expression. Moreover, we found that Tris DBA is an effective anti-myeloma agent alone or in combination with other targeted drugs and that it reverses hypoxia-induced drug resistance in myeloma.

摘要

尽管在新型靶向治疗方面取得了最新进展,但多发性骨髓瘤(MM)仍然是一种治疗上具有挑战性的无法治愈的疾病。重要细胞过程的调控及其与癌症的关联使Src成为MM一个有吸引力的靶点。我们提出了一种新策略,通过三(二亚苄基丙酮)二钯(Tris DBA)特异性抑制MM细胞中的Src,来改善MM的治疗并克服当前治疗药物的耐药性。Tris DBA可降低MM细胞的增殖,诱导G1期阻滞和凋亡。Tris DBA与蛋白酶体抑制剂显示出相加作用,比单独使用每种药物更能降低增殖、细胞周期信号传导并增加凋亡。Tris DBA通过抑制HIF1α表达克服了缺氧诱导的效应,如增强趋化性或对蛋白酶体抑制剂的耐药性。此外,我们发现Tris DBA单独使用或与其他靶向药物联合使用时是一种有效的抗骨髓瘤药物,并且它可逆转骨髓瘤中缺氧诱导的耐药性。

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