Stellettin B Sensitizes Glioblastoma to DNA-Damaging Treatments by Suppressing PI3K-Mediated Homologous Recombination Repair

Overview

Journal Adv Sci (Weinh)

Specialty Biomedical Engineering

Date 2022 Dec 1

PMID 36453577

Authors

Xin Peng

Shaolu Zhang

Yingying Wang

Zhicheng Zhou

Zixiang Yu

Zhenxing Zhong

Liang Zhang

Zhe-Sheng Chen

Francois X Claret

Moshe Elkabets

Feng Wang

Fan Sun

Ran Wang

Han Liang

Hou-Wen Lin

Dexin Kong

Affiliations

Soon will be listed here.

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.

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