BCL-2蛋白家族中在決定癌細(xì)胞接受治療后是否能生存或者腫瘤細(xì)胞的凋亡中起著很大的作用，促凋亡Bcl-2蛋白表達(dá)后會促使細(xì)胞走向凋亡,。然而,，癌癥細(xì)胞在接受治療后通過增加抗凋亡蛋白，中和促凋亡蛋白家庭成員,，以產(chǎn)生抗藥性,。
因此，抑制腫瘤細(xì)胞的抗凋亡策略將對臨床腫瘤治療帶來至關(guān)重要的改善,。
近日，Loren Walensky博士帶領(lǐng)的Dana-Farber癌癥研究所研究小組,，從促凋亡蛋白BCL-2的BIMBH3結(jié)構(gòu)域出發(fā)制造了一種新復(fù)合物,。這種化合物能競爭性地與抗凋亡蛋白結(jié)合導(dǎo)致癌細(xì)胞凋亡。
研究人員提出的一種新配方具有廣泛的靶向作用于Bcl-2家族,，可顯著提高臨床獲益,。（生物谷：Bioon.com）
doi:10.1172/JCI46231
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PMID:
stapled BIM peptide overcomes apoptotic resistance in hematologic cancers.
James L. LaBelle, Samuel G. Katz, Gregory H. Bird, Evripidis Gavathiotis, Michelle L. Stewart, Chelsea Lawrence, Jill K. Fisher, Marina Godes, Kenneth Pitter, Andrew L. Kung, Loren D. Walensky
Cancer cells subvert the natural balance between cellular life and death, achieving immortality through pathologic enforcement of survival pathways and blockade of cell death mechanisms. Pro-apoptotic BCL-2 family proteins are frequently disarmed in relapsed and refractory cancer through genetic deletion or interaction-based neutralization by overexpressed antiapoptotic proteins, resulting in resistance to chemotherapy and radiation treatments. New pharmacologic strategies are urgently needed to overcome these formidable apoptotic blockades. We harnessed the natural killing activity of BCL-2–interacting mediator of cell death (BIM), which contains one of the most potent BH3 death domains of the BCL-2 protein family, to restore BH3-dependent cell death in resistant hematologic cancers. A hydrocarbon-stapled peptide modeled after the BIM BH3 helix broadly targeted BCL-2 family proteins with high affinity, blocked inhibitory antiapoptotic interactions, directly triggered proapoptotic activity, and induced dose-responsive and BH3 sequence–specific cell death of hematologic cancer cells. The therapeutic potential of stapled BIM BH3 was highlighted by the selective activation of cell death in the aberrant lymphoid infiltrates of mice reconstituted with BIM-deficient bone marrow and in a human AML xenograft model. Thus, we found that broad and multimodal targeting of the BCL-2 family pathway can overcome pathologic barriers to cell death.
