Metformin and Androgen Receptor-Axis-Targeted (ARAT) Agents Induce Two PARP-1-Dependent Cell Death Pathways in...

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Androgen receptor-axis-targeted agents (ARATs) are key in treating prostate cancer (PC).
• Metformin's potential synergistic effects with ARATs require further investigation.
• Understanding the molecular mechanisms of combination therapy is crucial for improving PC treatment.

Purpose of the Study:

• To investigate if metformin enhances the anti-PC activity of abiraterone and enzalutamide.
• To elucidate the underlying molecular mechanisms of metformin and ARAT combination therapy in pre-clinical PC models.

Main Methods:

• Utilized complementary biological and molecular approaches in androgen-sensitive PC cell lines (LNCaP, VCaP).
• Assessed changes in androgen receptor (AR) and AR variant (ARv7) expression, cell proliferation, and cell death markers (PARP-1 cleavage, apoptosis).
• Analyzed lysosomal permeability, caspase-3 activity, and poly(ADP-ribose) (PAR) levels.

Main Results:

• Metformin alone decreased AR/ARv7 expression and induced cell death in both cell lines.
• Combination therapy with metformin and ARATs demonstrated superior inhibition of cell proliferation and enhanced induction of cell death compared to single agents.
• Combination treatments activated PARP-1-dependent, caspase-3-independent cell death pathways, involving increased PAR, nuclear AIF accumulation, and cathepsin G-mediated PARP-1 cleavage.

Conclusions:

• Metformin significantly enhances the efficacy of abiraterone and enzalutamide in pre-clinical prostate cancer models.
• The combination therapy operates through distinct PARP-1-dependent and caspase-3-independent mechanisms.
• These findings provide a strong rationale for evaluating metformin/ARAT combinations in clinical trials for castration-sensitive prostate cancer.