文章：

Omipalisib抗急性髓系白血病的效应：抑制PI3K/AKT/mTOR信号通路并抑制线粒体生物发生

Anti-leukemia effects of omipalisib in acute myeloid leukemia: inhibition of PI3K/AKT/mTOR signaling and suppression of mitochondrial biogenesis

原文发布日期：2023-10-11 

英文摘要：

Omipalisib (GSK2126458), a potent dual PI3K/mTOR inhibitor, is reported to exhibit anti-tumor effect in several kinds of cancers. More than 50% of acute myeloid leukemia (AML) patients display a hyperactivation of PI3K/AKT/mTOR signaling. We investigated the anti-proliferative effect of omipalisib in AML cell lines with varied genetic backgrounds. The OCI-AML3 and THP-1 cell lines had a significant response to omipalisib, with IC50 values of 17.45 nM and 8.93 nM, respectively. We integrated transcriptomic profile and metabolomic analyses, and followed by gene set enrichment analysis (GSEA) and metabolite enrichment analysis. Our findings showed that in addition to inhibiting PI3K/AKT/mTOR signaling and inducing cell cycle arrest at the G0/G1 phase, omipalisib also suppressed mitochondrial respiration and biogenesis. Furthermore, omipalisib downregulated several genes associated with serine, glycine, threonine, and glutathione metabolism, and decreased their protein and glutathione levels. In vivo experiments revealed that omipalisib significantly inhibited tumor growth and prolonged mouse survival without weight loss. Gedatolisib and dactolisib, another two PI3K/mTOR inhibitors, exerted similar effects without affecting mitochondria biogenesis. These results highlight the multifaceted anti-leukemic effect of omipalisib, revealing its potential as a novel therapeutic agent in AML treatment. 

摘要翻译： 

Omipalisib（GSK2126458）是一种强效的双重PI3K/mTOR抑制剂，据报道在多种癌症中表现出抗肿瘤效果。超过50%的急性髓系白血病（AML）患者存在PI3K/AKT/mTOR信号通路的过度激活。我们在不同遗传背景的AML细胞系中研究了omipalisib的抗增殖作用。OCI-AML3和THP-1细胞系对omipalisib表现出显著响应，其IC50值分别为17.45 nM和8.93 nM。通过整合转录组谱和代谢组分析，并进行基因集富集分析（GSEA）及代谢物富集分析，我们发现omipalisib除抑制PI3K/AKT/mTOR信号通路和诱导细胞周期停滞在G0/G1期外，还能抑制线粒体呼吸和生物合成。此外，omipalisib下调了多个与丝氨酸、甘氨酸、苏氨酸及谷胱甘肽代谢相关的基因，并降低了其蛋白质和谷胱甘肽水平。体内实验表明，omipalisib能显著抑制肿瘤生长并延长小鼠生存期，且未引起体重下降。另两种PI3K/mTOR抑制剂gedatolisib和dactolisib虽具有相似效果，但不影响线粒体生物合成。这些结果凸显了omipalisib多方面的抗白血病效应，揭示了其作为AML治疗新型药物的潜力。

原文链接：

Anti-leukemia effects of omipalisib in acute myeloid leukemia: inhibition of PI3K/AKT/mTOR signaling and suppression of mitochondrial biogenesis