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 PI3K α 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.

Stellettin B Induces Cell Death in Bladder Cancer Via Activating the Autophagy/DAPK2/Apoptosis Signaling Cascade

“…SP-2 also inhibited angiogenesis by reducing HIF-1α and VEGF in the glioblastoma cells [ 35 ], suggesting that SP-2 has the potential to regulate the HIF-1α-associated pathways and to change cellular and genomic regulation [ 55 , 56 , 57 ]. Recently, Peng et al found that SP-2 can sensitize glioblastoma cells to temozolomide chemotherapy by suppressing the PI3K-mediated homologous recombination repair [ 58 ]. The study indicated that SP-2 represents a promising drug candidate for drug combination.…”

Anticancer efficacy of hirsuteine against colorectal cancer by opposite modulation of wild-type and mutant p53

“…RNA-seq analysis was conducted according to our previous literature [ 17 ]. HCT-8 cells were exposed with DMSO or HST (32 μM) for 48 h. Total RNA from cells was extracted according to qRT-PCR and prepared total RNA was then sent to Novogene Co., Ltd (Beijing, China) for sequencing and analysis.…”

“…Flow cytometry was used to measure the cell cycle distribution and cell apoptosis as we reported before [ 17 ]. In brief, for cell cycle distribution analysis, after treated with HST or DMSO for 48 h, cells were collected, fixed, and permeabilized with 75% ice-cold ethanol at 4 °C overnight.…”

“…qRT-PCR was performed as our previous publication [ 14 , 17 ]. Total RNA was isolated from the cells treated with HST or DMSO for 48 h using TRIzol (Life Technologies, Carlsbad, CA, USA).…”

“…Co-IP assay was performed as previously described [ 17 ]. Prepared cells were lysed in lysis buffer (Beyotime, Shanghai, China) supplemented with phenylmethanesulfonyl fluoride (PMSF) and protease inhibitor cocktail at 4 °C for 30 min and pelleted by centrifugation (12,000 rpm, 20 min, 4 °C).…”