通过所谓的衰老物质有针对性地消除放射或化疗诱导的衰老细胞代表了一种减少肿瘤复发以及纤维化等治疗副作用的有前途的方法。我们筛选了来自海绵、内生真菌和高等植物的 178 种物质的内部库，并确定了它们对 DNA 损伤诱导的衰老 HCT116 结肠癌细胞的衰老活性。泛 PI3K 抑制剂渥曼青霉素及其临床衍生物 PX-866 被鉴定为 senolytics。 PX-866 在衰老的 HCT116、MCF-7 乳腺癌和 A549 肺癌细胞中有效诱导凋亡细胞死亡，无论衰老是由电离辐射还是化疗诱导，但在增殖细胞中则不然。其他 Pan-PI3K 抑制剂，例如 FDA 批准的药物 BAY80-6946（Copanlisib、Aliqopa®），也能有效且特异性地消除衰老细胞。有趣的是，只有同时抑制 PI3K I 类 α（使用 BYL-719（Alpelisib，Piqray®））和 δ（使用 CAL-101（Idelalisib，Zydelig®））亚型才足以诱导衰老作用，而单次应用这些亚型抑制剂没有效果。在分子水平上，PI3K 的抑制导致所有分析的肿瘤细胞系中 CDK 抑制剂 p21WAF1/CIP1 的蛋白酶体降解增加。这导致衰老肿瘤细胞及时诱导凋亡。总而言之，PI3K 抑制剂的衰老特性揭示了这些有前途的化合物的一个新维度，当与 DNA 损伤剂一起用于肿瘤联合治疗时，它们具有特别的潜力。© 2024。作者。

The targeted elimination of radio- or chemotherapy-induced senescent cells by so-called senolytic substances represents a promising approach to reduce tumor relapse as well as therapeutic side effects such as fibrosis. We screened an in-house library of 178 substances derived from marine sponges, endophytic fungi, and higher plants, and determined their senolytic activities towards DNA damage-induced senescent HCT116 colon carcinoma cells. The Pan-PI3K-inhibitor wortmannin and its clinical derivative, PX-866, were identified to act as senolytics. PX-866 potently induced apoptotic cell death in senescent HCT116, MCF-7 mammary carcinoma, and A549 lung carcinoma cells, independently of whether senescence was induced by ionizing radiation or by chemotherapeutics, but not in proliferating cells. Other Pan-PI3K inhibitors, such as the FDA-approved drug BAY80-6946 (Copanlisib, Aliqopa®), also efficiently and specifically eliminated senescent cells. Interestingly, only the simultaneous inhibition of both PI3K class I alpha (with BYL-719 (Alpelisib, Piqray®)) and delta (with CAL-101 (Idelalisib, Zydelig®)) isoforms was sufficient to induce senolysis, whereas single application of these inhibitors had no effect. On the molecular level, inhibition of PI3Ks resulted in an increased proteasomal degradation of the CDK inhibitor p21WAF1/CIP1 in all tumor cell lines analyzed. This led to a timely induction of apoptosis in senescent tumor cells. Taken together, the senolytic properties of PI3K-inhibitors reveal a novel dimension of these promising compounds, which holds particular potential when employed alongside DNA damaging agents in combination tumor therapies.© 2024. The Author(s).