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Science子刊:新型药物组合可有效治疗耐药性白血病

来源:生物谷 2016-05-19 23:10

图片来源:medicalxpress.com

2016年5月19日 讯 /生物谷BIOON/ --急性髓性白血病(AML)的患者或许找到了治疗疾病的希望,近日,刊登在国际杂志Science Translational Medicine上的一项研究报告中,来自伊丽莎-霍尔研究所(Walter and Eliza Hall Institute)的研究人员通过研究发现了一种新型方法可有效杀灭恶性增殖的白血病细胞。

细胞凋亡的过程即程序性细胞死亡,该过程是机体细胞的一种自然且必要的反应,用以约束人类细胞的增殖,然而在包括AML的多种癌症中细胞凋亡过程就被阻断了,从而就引发了细胞出现未受约束的增殖。文章中研究人员调查了靶向作用AML特殊类型的方法,他们希望可以在有效控制对患者机体健康细胞损伤的情况下来增加患者的治愈机会。

研究者Brumatti表示,传统的化疗方法,包括诱导细胞凋亡等都会出现患者较高的疾病复发率,比如在5年内完成治疗的患者中有50%的AML患者的病情会复发,而在复发的患者中又会有50%存活。这项研究中研究人员尝试了一种名为“蓝天”('blue sky')疗法,并且抑制了AML细胞发生凋亡,从而诱导细胞出现了另外一种名为坏死性凋亡(Necroptosis)的细胞死亡方式,研究者发现,坏死性凋亡细胞死亡途径相比细胞凋亡方法而言可以更加高效杀死AML细胞。

此前研究中,研究人员利用药物birinapant和恩利卡生(emricasan)的组合疗法来杀灭AML细胞,药物birinapant是一种新型的抗癌药物,而恩利卡生则是FDA批准的一种细胞凋亡抑制剂。研究者Silke教授说道,有人推测,细胞坏死性凋亡或许可以有效杀灭癌细胞,而我们的研究则清楚证实了坏死性凋亡的确是一种安全性可行性的方法。

最后研究者表示,癌细胞通常会对传统化疗诱导细胞凋亡的方法产生耐受性,而本文中所使用的新型化疗方法或许就可以治疗一些难以治疗的白血病,而这一研究也为众多白血病患者带来了极大的福音。(生物谷Bioon.com)

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The caspase-8 inhibitor emricasan combines with the SMAC mimetic birinapant to induce necroptosis and treat acute myeloid leukemia

Gabriela Brumatti1,2,*, Chunyan Ma1,2,*, Najoua Lalaoui1,2, Nhu-Y Nguyen3, Mario Navarro4, Maria C. Tanzer1,2, Jennifer Richmond5, Margherita Ghisi6, Jessica M. Salmon6, Natasha Silke1,2, Giovanna Pomilio3, Stefan P. Glaser1,2, Elisha de Valle7,8, Raffi Gugasyan7,8, Mark A. Gurthridge3, Stephen M. Condon9, Ricky W. Johnstone6, Richard Lock5, Guy Salvesen4, Andrew Wei3, David L. Vaux1,2, Paul G. Ekert1,2,10,†,‡ and John Silke1,2,†,‡

Resistance to chemotherapy is a major problem in cancer treatment, and it is frequently associated with failure of tumor cells to undergo apoptosis. Birinapant, a clinical SMAC mimetic, had been designed to mimic the interaction between inhibitor of apoptosis proteins (IAPs) and SMAC/Diablo, thereby relieving IAP-mediated caspase inhibition and promoting apoptosis of cancer cells. We show that acute myeloid leukemia (AML) cells are sensitive to birinapant-induced death and that the clinical caspase inhibitor emricasan/IDN-6556 augments, rather than prevents, killing by birinapant. Deletion of caspase-8 sensitized AML to birinapant, whereas combined loss of caspase-8 and the necroptosis effector MLKL (mixed lineage kinase domain-like) prevented birinapant/IDN-6556–induced death, showing that inhibition of caspase-8 sensitizes AML cells to birinapant-induced necroptosis. However, loss of MLKL alone did not prevent a caspase-dependent birinapant/IDN-6556–induced death, implying that AML will be less likely to acquire resistance to this drug combination. A therapeutic breakthrough in AML has eluded researchers for decades. Demonstrated antileukemic efficacy and safety of the birinapant/emricasan combination in vivo suggest that induction of necroptosis warrants clinical investigation as a therapeutic opportunity in AML.

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