Overexpression of the prosurvival protein BCL-2 contributes to malignant cell initiation, progression and resistance to treatment. Agents that function as its natural antagonists targeting BCL-2 must provide therapeutic benefit. In SW1990 pancreatic cancer cells, amplified BCL-2 was observed, which was believed to offer advantages for malignant cell survival and lead to poor patient outcome. Using structure-based virtual ligand screening, luteolin was found to be a natural small-molecule inhibitor of BCL-2, which exhibited dose–response proapoptosis activity in a BCL-2 dependent manner in vitro. The cellular thermal shift assay (CETSA) and notably competitive binding assay by the microscale thermophoresis (MST) method provided the evidence that this flavonoid directly bound to BCL-2. Mechanistic studies revealed that luteolin (compound 1) displaced BAX from the hydrophobic cleft of BCL-2, allowing mitochondrial permeabilization, and inducing SW1990 cancer cells to die. Meanwhile, luteolin represented significant tumor growth inhibition in an SW1990 xenograft model. Collectively, luteolin is rationally proved to trigger SW1990 cells to apoptosis by targeting BCL-2, and may serve as a potential agent for this cancer therapy.

中文翻译：

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饮食化合物木犀草素通过靶向BCL-2 †抑制胰腺癌的生长

生存蛋白BCL-2的过表达有助于恶性细胞的起始，进展和对治疗的抵抗力。充当针对BCL-2的天然拮抗剂的药物必须提供治疗益处。在SW1990胰腺癌细胞中，观察到扩增的BCL-2，据信它对恶性细胞存活具有优势，并导致不良的患者预后。使用基于结构的虚拟配体筛选，发现木犀草素是BCL-2的天然小分子抑制剂，其在体外以BCL-2依赖性方式表现出剂量反应促凋亡活性。。细胞热位移测定法（CETSA），尤其是通过微尺度热泳（MST）方法进行的竞争性结合测定法提供了这种类黄酮直接与BCL-2结合的证据。机理研究表明，木犀草素（化合物1）使BAX脱离了BCL-2的疏水缝隙，从而使线粒体通透并诱导SW1990癌细胞死亡。同时，木犀草素在SW1990异种移植模型中表现出显着的肿瘤生长抑制作用。集体地，木犀草素被合理地证明可以通过靶向BCL-2触发SW1990细胞凋亡，并且可以作为这种癌症治疗的潜在药物。