A Computational and In Vitro Appraisal of Ostarine to Target Androgen Receptor in Glioma C6 Cells

Area of Science:

• Neuro-oncology
• Molecular Endocrinology
• Cancer Therapeutics

Background:

• Gliomas are primary brain tumors originating from glial cells, representing the majority of central nervous system (CNS) malignancies.
• Androgen receptor (AR) signaling is implicated in tumor growth and altered in various cancers, including glioma.
• Targeting AR for glioma treatment is of interest, but traditional antagonists are limited by glioma's heterogeneity.

Purpose of the Study:

• To investigate the potential of selective androgen receptor modulators (SARMs) as a therapeutic strategy for glioma.
• To evaluate the binding affinity and efficacy of SARMs against glioma cells.
• To identify a SARM with promising anti-glioma activity.

Main Methods:

• Computational screening of 20 SARMs using AutoDock vina for binding affinity analysis.
• Molecular dynamics (MD) simulations and MM-PBSA analysis to assess binding stability.
• In vitro assays including IC50 determination, cell viability, migration, and invasion assays using C6 glioma cells.

Main Results:

• Ostarine (MK-2866) demonstrated high binding affinity (-9.4 Kcal/mol) to the AR N-terminal domain (NTD).
• MD simulations and MM-PBSA confirmed strong and stable binding of Ostarine to AR.
• Ostarine showed a twofold increase in C6 cell inhibition compared to Bicalutamide and reduced cell viability, migration, and invasion.

Conclusions:

• Ostarine acts as a potent AR antagonist with significant chemotherapeutic potential against glioma.
• SARMs, exemplified by Ostarine, represent a promising therapeutic avenue for managing glioma propagation.
• Further studies are warranted to explore Ostarine's efficacy in more aggressive glioma models.