雷达51
替莫唑胺
同源重组
癌症研究
DNA损伤
DNA修复
非同源性末端接合
医学
生物
DNA
胶质母细胞瘤
遗传学
作者
Xin Peng,Shaolu Zhang,Yingying Wang,Zhicheng Zhou,Zixiang Yu,Zhenxing Zhong,Liang Zhang,Zhe‐Sheng Chen,François X. Claret,Moshe Elkabets,Feng Wang,Fan Sun,Ran Wang,Han Liang,Wei‐Hua Jiao,Dexin Kong
标识
DOI:10.1002/advs.202205529
摘要
Glioblastoma (GBM) is the most aggressive type of cancer. Its current first-line postsurgery regimens are radiotherapy and temozolomide (TMZ) chemotherapy, both of which are DNA damage-inducing therapies but show very limited efficacy and a high risk of resistance. There is an urgent need to develop novel agents to sensitize GBM to DNA-damaging treatments. Here it is found that the triterpene compound stellettin B (STELB) greatly enhances the sensitivity of GBM to ionizing radiation and TMZ in vitro and in vivo. Mechanistically, STELB inhibits the expression of homologous recombination repair (HR) factors BRCA1/2 and RAD51 by promoting the degradation of PI3Kα through the ubiquitin-proteasome pathway; and the induced HR deficiency then leads to augmented DNA damage and cell death. It is further demonstrated that STELB has the potential to rapidly penetrate the blood-brain barrier to exert anti-GBM effects in the brain, based on zebrafish and nude mouse orthotopic xenograft tumor models. The study provides strong evidence that STELB represents a promising drug candidate to improve GBM therapy in combination with DNA-damaging treatments.
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