Gold Cluster Capped with a BCL-2 Antagonistic Peptide Exerts Synergistic Antitumor Activity in Chronic Lymphocytic Leukemia Cells

文献类型： 外文期刊

第一作者： Yao, Yawen

作者： Yao, Yawen;Lu, Cao;Gao, Liang;Cao, Kai;Gao, Xueyun;Yuan, Qing;Yao, Yawen;Lu, Cao;Gao, Liang;Cao, Kai;Gao, Xueyun;Yuan, Qing;Yuan, Hui;Zhang, Xiangchun

作者机构：

关键词： chronic lymphocytic leukemia; gold clusters; BCL-2 antagonist peptide; thioredoxin reductase; mitochondrial pathway of apoptosis

期刊名称：ACS APPLIED MATERIALS & INTERFACES （ 影响因子：9.229； 五年影响因子：9.57 ）

ISSN： 1944-8244

年卷期： 2021 年 13 卷 18 期

页码：

收录情况： SCI

摘要： Chronic lymphocytic leukemia (CLL) is still incurable by conventional chemotherapy due to the resistance to apoptosis. We have previously found that a peptide-capped gold cluster (Au(25)Sv(9)) can target on the aberrant oxidative stress in CLL cells to specially inhibit thioredoxin reductase (TrxR) activity, resulting in significant apoptosis. However, the required doses of the gold cluster for inducing apoptosis are high, restricting its potential for further applications. Notably, the most recent studies suggested that CLL cells overexpressed antiapoptotic BCL-2 protein to prevent chemotherapy-induced apoptosis, indicating that BCL-2 could be a promising target for CLL therapy. Regrettably, the nonmitochondrial-targeted Au(25)Sv(9) has little effect on BCL-2. In this study, we successfully screened a modified BADBH3 peptide (B1P) that could antagonize BCL-2 protein in CLL cells. We found that B1P could effectively sensitize MEC-1 cells to a subliminal dose of Au(25)Sv(9). To simplify the treatment regimen, we directly fabricated a gold cluster capped with the B1P peptides by one-step synthesis to integrate the BCL-2 antagonistic activity into the gold the cluster, named BGC. We already found that low doses of BGC could significantly induce more apoptosis in MEC-1 cells than equivalent doses of the Au(25)Sv(9) cluster or B1P peptide alone. Mechanistically, in addition to the inherent inhibitory effect of gold clusters on TrxR activity, BGC could bind to BCL-2 on mitochondria and activate the BCL-2 family-mediated mitochondrial apoptosis cascade more effectively. These results demonstrated that antagonizing the overexpressed BCL-2 in CLL cells, together with inhibiting TrxR simultaneously by a single gold cluster, is a promising strategy for the treatment of CLL cells. This study will provide a paradigm and reference for the development of functionalized gold clusters with rationally designed peptides, and opens up a new opportunity for the treatment of CLL in clinical settings.

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