In a recent review published in Nutrients, authors compared the cellular mechanisms of soy isoflavones, genistein, daidzein, and equol, focusing on their roles in prostate cancer (PCa) prevention and treatment.
Study: The Use of Soy Isoflavones in the Treatment of Prostate Cancer: A Focus on the Cellular Effects. Image Credit: aito29/Shutterstock.com
Background
Globally, PCa incidence and mortality show geographic variations, with East Asia having lower rates than Western countries.
This variation is linked to dietary differences, particularly soy isoflavone intake, which is higher in Asian diets. Studies suggest soy isoflavones may reduce PCa risk, with migrant Japanese men in the United States (U.S.) showing similar PCa rates to Native Americans.
While preclinical studies highlight potential mechanisms of soy isoflavones in PCa carcinogenesis, clinical evidence remains sparse. PCa’s characteristics, including its high incidence, long latency, and identifiable markers, make it a prime candidate for chemoprevention through soy isoflavones.
Further research is needed to validate the promising preclinical results with clinical data, establishing the efficacy of soy isoflavones in the prevention and treatment of PCa.
Soy isoflavones: A diverse world of phytochemicals
Soybeans, a rich source of isoflavones, undergo fermentation to produce aglucones like daidzein, genistein, and glycitein. Genistein and daidzein are the primary focus due to their significant presence and biological importance.
Glycitein, albeit studied less, has shown potential benefits in certain cancers. Unique to daidzein is its conversion to equol by gut bacteria, a process occurring more commonly in Asians than Western populations.
Equol's enantiomer S-equol shows a selective affinity for the estrogen receptor β (ER-β), differing from genistein and daidzein in chemical characteristics and biological effects, such as enhanced antioxidant activity.
Intricate cellular pathways and mechanisms
The biological actions of genistein, daidzein, and equol involve complex cellular pathways, including androgen and estrogen receptors, cell proliferation and angiogenesis, cycle regulation, and metastasis. These isoflavones also exhibit anti-inflammatory, antioxidant, and potential anticancer epigenetic activities.
Differences between in vitro and in vivo Studies
A key distinction in isoflavone research lies in the disparity between in vitro and in vivo studies. In vitro studies often use lower doses and reveal more pronounced effects than in vivo experiments, where doses vary based on the animal model.
This difference is crucial when interpreting the results across different sections of the study.
Modulation of hormone-driven carcinogenesis
In the human prostate, estrogen receptor β (ER-β) is predominant and interacts with soy isoflavones like genistein and equol. These isoflavones structurally resemble estrogen, allowing them to bind to ER-β and modulate its function. Genistein and equol's affinity for ER-β is similar to estrogen's, albeit genistein requires higher concentrations for transcriptional activation.
Importantly, activating ER-β can downregulate androgen receptors (AR), reducing prostate tissue's response to androgens and decreasing prostate-specific antigen (PSA) production. This effect varies with PCa cell types and is evident in cell studies and animal models.
Additionally, equol binds dihydrotestosterone, preventing AR activation and promoting AR degradation, while genistein also contributes to AR degradation through heat shock proteins. Although genistein can decrease AR gene expression in vitro, equol does not show this effect in animal studies.
Impact on cancer cell growth
Genistein inhibits PCa cell growth regardless of AR status. It disrupts growth factor tyrosine kinase (TK) activity, which is crucial in cancer treatment. Additionally, genistein affects the expression of ErbB receptor family proteins and insulin growth factor 1 (IGF-1) signaling, critical in cancer progression and metastasis.
Genistein and other isoflavones' suppression of various molecular pathways indicates their potential to inhibit PCa cell growth.
Influence on cell cycle regulation
Isoflavones, particularly genistein, can arrest the cell cycle in PCa cells, impacting cyclin-dependent kinases (CDKs) and cyclins.
This regulatory action inhibits cell growth and proliferation, showcasing the anti-cancer potential of isoflavones in different cell cycle phases.
Angiogenesis and its inhibition
Isoflavones hinder angiogenesis, a key process in tumor growth and expansion. By inhibiting growth factors like vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) and reducing the expression of inflammatory cytokines, isoflavones like genistein and equol play a crucial role in controlling angiogenesis, thereby limiting tumor progression.
Invasion and metastasis of tumor cells
Isoflavones have shown promise in inhibiting stages of metastasis, such as epithelial-to-mesenchymal transition (EMT) and the destruction of the extracellular matrix (ECM). They impact various enzymes and proteins, reducing prostate cancer cells' invasive and metastatic potential.
Antioxidant effects of isoflavones
Under normal conditions, free radicals and reactive oxygen species (ROS) are produced during cellular respiration. Stress or disease can increase their levels, causing cellular damage. Soy isoflavones, particularly equol, combat this oxidative stress by enhancing the body's antioxidant enzymes like superoxide dismutase (SOD) and catalase.
Genistein, a type of soy isoflavone, increases these antioxidants in cells, reducing ROS and nitric oxide, another oxidative agent. Equol is particularly effective in this role, showing superior antioxidant activity by inhibiting nitric oxide synthesis more effectively.
Anti-inflammatory actions in cancer
Inflammation plays a dual role in cancer, and isoflavones like genistein have shown effects on tumor-associated macrophages (TAMs), inflammatory mediators, and cytokines. By modulating these factors, isoflavones potentially hinder cancer progression and metastasis.
Epigenetic modifications
Isoflavones, especially genistein, impact deoxyribonucleic acid (DNA) methylation and histone modifications, which are crucial in gene regulation.
They also regulate microribonucleic acids (miRNAs), which are involved in cell growth and survival, highlighting their role in epigenetic modifications associated with cancer.
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