Molecular Efficacy of Gnetin C as Dual-Targeted Therapy for Castrate-Resistant Prostate Cancer

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Castrate-resistant prostate cancer (CRPC) often develops resistance to enzalutamide (Enz) through androgen receptor splice variant (AR-V7) expression.
• Non-AR-driven signaling pathways, including metastasis-associated protein 1 (MTA1) overexpression, also contribute to CRPC progression.
• Natural compounds offer potential synergistic effects when combined with conventional anticancer drugs, potentially enhancing efficacy and reducing toxicity.

Purpose of the Study:

• To investigate the in vitro and in vivo anticancer effects of Gnetin C (GnC) as a monotherapy and in combination with Enz against CRPC.
• To elucidate the molecular mechanisms underlying the combined therapeutic effects, focusing on AR and MTA1 signaling pathways.

Main Methods:

• In vitro assessments included cell viability, clonogenic survival, and migration assays using 22Rv1 CRPC cells.
• AR and MTA1 expression levels were analyzed using western blot, RT-PCR, and immunohistochemistry (IHC).
• In vivo efficacy was evaluated through tumor growth assessment using bioluminescent imaging in preclinical models.

Main Results:

• GnC, both alone and in combination with Enz, significantly inhibited cell viability, clonogenic survival, and migration in 22Rv1 cells.
• The combined treatment effectively suppressed both AR and MTA1 expression.
• In vivo studies demonstrated that GnC and Enz combination therapy inhibited tumor proliferation and angiogenesis while inducing apoptosis.

Conclusions:

• Gnetin C, alone and combined with enzalutamide, demonstrates significant potential in inhibiting AR- and MTA1-driven tumor progression in advanced CRPC.
• This combination therapy represents a promising novel therapeutic strategy for managing castrate-resistant prostate cancer.