Faculty, Staff and Student Publications
Publication Date
1-1-2023
Journal
Advanced Science
Abstract
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.
Keywords
Animals, Mice, Humans, Glioblastoma, Recombinational DNA Repair, Dacarbazine, Phosphatidylinositol 3-Kinases, Antineoplastic Agents, Alkylating, Zebrafish, Drug Resistance, Neoplasm, Brain Neoplasms, Temozolomide, Triterpenes, DNA Damage, DNA‐damaging treatment, glioblastoma, homologous recombination repair, PI3K, stellettin B
DOI
10.1002/advs.202205529
PMID
36453577
PMCID
PMC9875605
PubMedCentral® Posted Date
12-1-2022
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons