The Cellular Effects and Clinical Potential of Soy Isoflavones in Prostate Cancer

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Prostate cancer (PCa) exhibits geographical variations in incidence and mortality, with East Asia having lower rates compared to Western countries. This disparity, linked to migration effects, particularly among Japanese men in the United States, underscores the role of environmental factors, notably dietary habits. Epidemiological studies suggest an inverse relationship between soy isoflavone intake and PCa risk, setting the stage for investigating the cellular effects and clinical potential of soy isoflavones in PCa prevention.

Soy Isoflavones: Diversity and Metabolism:
Soybeans, the primary source of isoflavones, undergo fermentation to produce isoflavone aglucon, comprising genistein, daidzein, and glycitein. Glycitein, although less studied, demonstrates beneficial effects in gastrointestinal and breast cancers. Daidzein’s conversion to equol by gut microflora is a notable feature, with equol exhibiting unique chemical characteristics and greater antioxidant activity. This review focuses on genistein, daidzein, and equol due to their relevance in PCa.

Cellular Mechanisms of Soy Isoflavones in Prostate Cancer:
The cellular effects of genistein, daidzein, and equol involve complex interactions with various pathways, including androgen- and estrogen-driven processes, cell proliferation, angiogenesis, metastasis, anti-inflammatory responses, antioxidant properties, and potential anticancer epigenetic activity. These effects align with the hallmarks of cancer, providing a conceptual framework for understanding the impact of soy isoflavones on prostate cancer cells.

Modification of Androgen- and Estrogen-Mediated Carcinogenesis:
Genistein and equol exhibit structural similarities to estrogen, competing for estrogen receptors (ER), particularly ER-β found predominantly in the prostate. The interaction with ER-β leads to downregulation of the androgen receptor (AR), resulting in reduced prostate-specific antigen (PSA) production. Equol’s unique anti-androgenic effects, including DHT binding and AR degradation, highlight its potential in modulating prostate cancer growth. The dosage variations in in vitro and in vivo studies are crucial considerations for interpreting the results.

Inhibition of Cancer Cell Growth:
Genistein demonstrates an inhibitory effect on prostate cancer cell growth, irrespective of AR status, affecting androgen-independent and androgen-sensitive cell lines. High doses of genistein inhibit growth factor tyrosine kinase activity and suppress EGFR and ErbB receptors. The inhibition of IGF-1-stimulated cell growth, modulation of PI3K/AKT and RAS/MAPK pathways, and the induction of apoptosis further contribute to the anti-cancer properties of genistein.

Effects on Cell Cycle Regulation:
Genistein-induced cell cycle arrest, particularly in the G2/M phase, involves the downregulation of cyclin B1, upregulation of p21WAF1, and induction of apoptosis. The interference with cyclin-dependent kinases (CDKs) and cyclins at various concentrations emphasizes the regulatory role of soy isoflavones in controlling cell cycle progression. Equol also exhibits similar effects on cell cycle regulation, reinforcing the potential therapeutic impact of soy isoflavones in prostate cancer.

Angiogenesis:
Angiogenesis, the formation of new blood vessels, is a crucial process for tumor growth and metastasis. Isoflavones, particularly genistein, daidzein, and equol, exert inhibitory effects on angiogenesis. This includes downregulation of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), and interleukin-8 (IL-8). Genistein’s impact on VEGF expression through hypoxia-inducible factor-1α (HIF-1α) and the inhibition of VEGF receptors in human endothelial cells highlight its anti-angiogenic potential. Equol also demonstrates inhibitory effects on angiogenesis via the MAPK pathway.

Tumor Cell Invasion and Cancer Metastasis:
Isoflavones exhibit significant potential in inhibiting various phases of metastasis, including epithelial-to-mesenchymal transition (EMT), destruction of the extracellular matrix (ECM), and mesenchymal-to-epithelial transition (MET). Genistein, in particular, inhibits invasive growth through reversing EMT and suppressing matrix metalloproteinases (MMPs), crucial enzymes in tumor invasion. The inhibitory effects on metastasis extend to AKR1C3, COX-2, osteopontin, and prostaglandins, contributing to reduced migration and metastatic potential in both in vitro and in vivo models.

Antioxidant Effect:
Soy isoflavones, particularly equol, demonstrate robust antioxidant properties by modulating the expression of cellular enzymes and protecting cells from free radicals and reactive oxygen species (ROS). Genistein, through AMP-activated protein kinase (AMPK) and PTEN pathways, enhances antioxidant enzymes, suppresses ROS levels, and inhibits nitric oxide (NO) production.

Anti-Inflammatory Effect:
The impact of genistein on tumor-associated macrophages (TAMs) emerges as a crucial anti-inflammatory mechanism. Genistein reduces TAMs, leading to a decrease in blood vessel density and tumor size. Equol and genistein interfere with interleukin-10 (IL-10) and prostaglandin E2, further highlighting their anti-inflammatory potential.

Epigenetics:
Genistein’s role in epigenetic regulation is notable, inhibiting DNA methylation and histone modifications. It influences tumor suppressor genes, including BRCA1, BTG3, and RASSF1A, by reducing methylation. Additionally, genistein regulates microRNAs involved in cell growth and survival, contributing to the inhibition of oncogenes and tumor growth. Equol also participates in epigenetic regulation, inhibiting cancer cell proliferation through the polyadenylation of small nucleolar RNAs (snoRNAs).

Conclusion:

This comprehensive exploration underscores the multifaceted impact of soy isoflavones on prostate cancer at the cellular level. From angiogenesis inhibition to anti-inflammatory responses, antioxidant effects, and epigenetic regulation, soy isoflavones demonstrate promising potential in modulating key processes implicated in prostate cancer progression. Further research and clinical studies are essential to fully unravel the therapeutic implications of soy isoflavones in prostate cancer management.


reference link : https://www.mdpi.com/2072-6643/15/23/4856

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