# Bioactive Natural Products Targeting Androgen Receptor Signaling in Prostate Cancer: A Systematic Review

## TL;DR

This review explores natural compounds that can target the androgen receptor in prostate cancer, offering potential new treatments for drug-resistant cases.

## Contribution

The study systematically identifies and categorizes bioactive natural products that modulate the androgen receptor signaling pathway in prostate cancer.

## Key findings

- Natural compounds like neoisoliquiritin and α-terthienyl suppress androgen receptor activity and nuclear translocation.
- α-mangostin degrades AR-V7, a resistant variant of the androgen receptor, while manzamine A inhibits AR biosynthesis via E2F8.
- Compounds from Annona muricata and (-)-epicatechin modulate resistance through 5-α-reductase inhibition and ZIP9 activation.

## Abstract

Prostate cancer is a leading cause of death in men, often because the disease becomes resistant to standard therapies that target male hormones. This resistance occurs when the cancer’s “control switch”, known as the androgen receptor, continues to drive growth despite treatment. This systematic review examines 15 recent studies to identify natural compounds that can successfully block this switch through various biological methods. We found that these natural substances can deactivate the receptor, break down its resistant forms, and prevent it from reaching the cell’s nucleus. The emergence of resistance, particularly in castration-resistant prostate cancer (CRPC), necessitates the exploration of innovative therapeutic approaches. This systematic review consolidates contemporary evidence regarding natural products as potential bioactive alternatives for modulating the androgen receptor (AR) signaling axis. Rather than providing a definitive clinical roadmap, this work establishes a preclinical framework for identifying substances that may deactivate the receptor, break down its resistant forms, or prevent nuclear translocation.

Background: Prostate cancer remains a leading cause of male cancer-related mortality, largely driven by the dysregulated activation of the androgen receptor (AR) signaling pathway. The emergence of resistance, particularly in castration-resistant prostate cancer (CRPC), necessitates the discovery of innovative therapeutic approaches. This systematic review aims to consolidate contemporary evidence regarding natural products as bioactive alternatives capable of targeting the AR signaling axis. Methods: Adhering to PRISMA guidelines, a systematic search was conducted across PubMed, Scopus, and ScienceDirect databases. The review identified and qualitatively analyzed 15 original research studies that investigated the efficacy and mechanisms of various natural compounds in modulating AR signaling. Results: The analysis reveals that natural products deactivate the AR signaling axis through diverse mechanisms. Neoisoliquiritin and α-terthienyl were found to suppress AR expression, activity, and nuclear translocation. Notably, α-mangostin facilitates the degradation of the AR-V7 splice variant, a key driver of treatment resistance. Manzamine A inhibits AR biosynthesis by targeting the transcription factor E2F8. Furthermore, alternative pathways are modulated through 5-α-reductase inhibition (Annona muricata compounds) and the activation of the non-classical membrane receptor ZIP9 by (-)-epicatechin to induce apoptosis. Conclusions: The emergence of resistance, particularly in castration-resistant prostate cancer (CRPC), necessitates the exploration of innovative therapeutic approaches. This systematic review consolidates contemporary evidence regarding natural products as potential bioactive alternatives for modulating the androgen receptor (AR) signaling axis. Rather than providing a definitive clinical roadmap, this work establishes a preclinical framework for identifying substances that may deactivate the receptor, break down its resistant forms, or prevent nuclear translocation.