@article{86f6ffb835a64f22bd881eb2f92f4669,
title = "Stellettin B Sensitizes Glioblastoma to DNA-Damaging Treatments by Suppressing PI3K-Mediated Homologous Recombination Repair",
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 = "DNA-damaging treatment, glioblastoma, homologous recombination repair, PI3K, stellettin B",
author = "Xin Peng and Shaolu Zhang and Yingying Wang and Zhicheng Zhou and Zixiang Yu and Zhenxing Zhong and Liang Zhang and Chen, {Zhe Sheng} and Claret, {Francois X.} and Moshe Elkabets and Feng Wang and Fan Sun and Ran Wang and Han Liang and Lin, {Hou Wen} and Dexin Kong",
note = "Funding Information: The authors thank Ms. Shuyue Dai, Ms. Xinmiao Wang, Mr. Han Guo, and Mr. Hao Lu of School of Pharmacy, Tianjin Medical University for assistance in data analysis, and Dr. Kamalika Mojumdar of Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center for editorial assistance. SF295 and SF268 cell lines were kindly provided by the National Cancer Institute, National Institutes of Health, USA. The primary patient‐derived GBM cell line SHG140 was kindly provided by Dr. Zhennan Tao of Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University. The primary patient‐derived GBM cell line DT001 was provided by Dr. Yuxiang Dai of Department of Neurosurgery, the Affiliated Drum Tower Hospital, School of Medicine, Nanjing University. The pcDNA3.1 and HA‐I‐SceI plasmids and the U2OS‐EJ5‐GFP cell line were kindly provided by Professor Lei Shi, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University. The image of marine sponge in Figure 8 was kindly provided by {\textcopyright} Philippe & Guido Poppe— www.poppe‐images.com . This project was supported by grants from the National Natural Science Foundation of China (82073890, 81673464, and 82061148017, to D.K.; 22137006, to H.W.L.; 82073713, to F.S.; 82204460, to X.P.), Fellowship of China Postdoctoral Science Foundation (2021M702464 to X.P.), Postgraduate Innovation Fund of 13th Five‐Year comprehensive investment of Tianjin Medical University (YJSCX201806 to X.P.). Jaspis stellifera Publisher Copyright: {\textcopyright} 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.",
year = "2022",
month = jan,
day = "1",
doi = "10.1002/advs.202205529",
language = "English",
journal = "Advanced Science",
issn = "2198-3844",
publisher = "Wiley-VCH Verlag",
}