Abstract
Glioblastoma (GBM) is the most common primary brain tumor with median survival of approximately one year. This dismal poor prognosis is due to resistance to currently available chemotherapeutics; therefore, new cytotoxic agents are urgently needed. In the present study, we reported the cytotoxicity of toosendanin (TSN) in the GBM U87 and C6 cell lines in vitro and in vivo. By using the MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assay, flow cytometry analysis, and Western blot, we found that TSN inhibited U87 and C6 cell proliferation and induced apoptosis at a concentration as low as 10 nM. Administration of TSN also reduced tumor burden in a xenograft model of athymic nude mice. Pharmacological and molecular studies suggested that estrogen receptor β (ERβ) and p53 were prominent targets for TSN. GBM cell apoptosis induced by TSN was a stepwise biological event involving the upregulation of ERβ and contextual activation of functional p53. Collectively, our study indicates, for the first time, that TSN is a candidate of novel anti-cancer drugs for GBM. Furthermore, ERβ and p53 could act as predictive biomarkers for the sensitivity of cancer to TSN.
Highlights
Glioblastoma (GBM) is the most frequent and life-threatening primary malignancy in the central nervous system
The results showed that TSN inhibited the growth of human GBM U87 cells in a dose- and time-dependent manner (Figure 1,C)
The addition of TSN further enhanced the apoptotic response (Figure 5C,D, Figure S3D). These findings indicated that upregulation of estrogen receptor β (ERβ) and p53, two major tumor suppressors in the central nervous system, are both required for the pro-apoptotic action of TSN in GBM
Summary
Glioblastoma (GBM) is the most frequent and life-threatening primary malignancy in the central nervous system. The ERα gene ( known as ESR1) is located on chromosome 6q25.1 and encodes ERα protein, and its homologous counterpart ERβ ( known as ESR2) is located on chromosome 14q23.2 These two ERs share 97% homology in their DNA binding domains, they exhibit contradictory biological functions. A genome-wide study has indicated that ERα and ERβ proteins differentially regulate genes involved in cell growth and survival. This unique molecular property of ERs highlights a therapeutic strategy that downregulating ERα and upregulating ERβ may be beneficial in treating cancers that express ERs [15,16,17]. We identified a specific association between ERβ and the p53 status in response to TSN treatment in GBM. It is essential to determine the patient’s ERβ and p53 status before treating GBM with a TSN-based strategy
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