Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China.
Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin, 300070, China.
Adv Sci (Weinh). 2023 Jan;10(3):e2205529. doi: 10.1002/advs.202205529. Epub 2022 Dec 1.
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.
胶质母细胞瘤（GBM）是最具侵袭性的癌症类型。目前，其术后一线治疗方案是放疗和替莫唑胺（TMZ）化疗，这两种方法均为诱导 DNA 损伤的疗法，但疗效非常有限，而且耐药风险很高。因此，迫切需要开发新型药物来提高 GBM 对 DNA 损伤治疗的敏感性。本研究发现，三萜类化合物斯蒂林 B（STELB）可显著增强 GBM 对体外和体内电离辐射和 TMZ 的敏感性。在机制上，STELB 通过泛素-蛋白酶体途径促进 PI3Kα 的降解来抑制同源重组修复（HR）因子 BRCA1/2 和 RAD51 的表达；诱导的 HR 缺陷继而导致 DNA 损伤和细胞死亡增加。基于斑马鱼和裸鼠原位异种移植肿瘤模型，进一步证明 STELB 具有穿透血脑屏障在大脑中发挥抗 GBM 作用的潜力。该研究为 STELB 与 DNA 损伤治疗联合改善 GBM 治疗提供了有力证据，表明其是一种很有前途的候选药物。
