JCI：新开发的复合物触发肿瘤细胞死亡

BCL-2蛋白家族中在决定癌细胞接受治疗后是否能生存或者肿瘤细胞的凋亡中起着很大的作用，促凋亡Bcl-2蛋白表达后会促使细胞走向凋亡。然而，癌症细胞在接受治疗后通过增加抗凋亡蛋白，中和促凋亡蛋白家庭成员，以产生抗药性。

因此，抑制肿瘤细胞的抗凋亡策略将对临床肿瘤治疗带来至关重要的改善。

近日，Loren Walensky博士带领的Dana-Farber癌症研究所研究小组，从促凋亡蛋白BCL-2的BIMBH3结构域出发制造了一种新复合物。这种化合物能竞争性地与抗凋亡蛋白结合导致癌细胞凋亡。

研究人员提出的一种新配方具有广泛的靶向作用于Bcl-2家族，可显著提高临床获益。

doi:10.1172/JCI46231
PMC:
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.