Enzalutamide effectively inhibits the growth of meningiomas via p21-dependent senescence induction.

BACKGROUND: Meningiomas are the most common central nervous system tumors and are primarily managed through surgical resection and radiation therapy. The development of meningioma is associated with sex steroid hormone-related risk factors. However, anti-sex steroid hormone therapy in meningiomas is still unclear. METHODS: Expression levels of sex steroid hormone receptors were determined in meningioma tissues and cell lines via quantitative PCR. The effects of androgen receptor inhibitor (enzalutamide; ENZ) on meningioma cell growth were investigated via cell viability test, cell cycle analysis and senescence-associated β-galactosidase activity. RESULTS: Androgen receptor (AR) expression was observed in all WHO grade meningiomas. In comparison, progesterone receptor (PR) expression was detected mainly in WHO grade 1 meningiomas but was absent in grade 3 meningiomas. Targeting AR with ENZ significantly inhibited the growth of malignant meningioma cells (HKBMM and IOMM-Lee). Malignant meningioma cells, particularly IOMM-Lee cells, were sensitive to ENZ. ENZ induced cell cycle arrest and increased the sub-G1 population in both malignant meningioma cell lines. Elevated cyclin D1 expression and loss of replicative potential via the reduction of Ki-67 nuclei were also observed. ENZ induced senescence-associated β-galactosidase activity, associated with up-regulation of p21 and down-regulation of the anti-apoptotic protein Mcl-1, in both malignant meningioma cell lines. Additionally, down-regulation of AR-positive cells and AR target genes, including EDN2, TMPRSS2, and KLK3, was observed only in HKBMM cells expressing AR. CONCLUSIONS: Our findings suggest that ENZ induces a senescence-like phenotype in malignant meningioma cells via p21-dependent induction. Lastly, ENZ may serve as a promising targeted therapy for meningiomas, particularly for aggressive subtypes or in cases of recurrence.