期刊
ADVANCED SCIENCE
卷 10, 期 3, 页码 -出版社
WILEY
DOI: 10.1002/advs.202205529
关键词
DNA-damaging treatment; glioblastoma; homologous recombination repair; PI3K; stellettin B
The triterpene compound STELB enhances the sensitivity of GBM to DNA-damaging treatments by inhibiting the expression of HR factors and can penetrate the blood-brain barrier to exert anti-GBM effects.
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 PI3K alpha 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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