Abstract
Soy isoflavones have been documented as dietary nutrients broadly classified as “natural agents” which plays important roles in reducing the incidence of hormone-related cancers in Asian countries, and have shown inhibitory effects on cancer development and progression in vitro and in vivo, suggesting the cancer preventive or therapeutic activity of soy isoflavones against cancers. Emerging experimental evidence shows that isoflavones could induce cancer cell death by regulating multiple cellular signaling pathways including Akt, NF-κB, MAPK, Wnt, androgen receptor (AR), p53 and Notch signaling, all of which have been found to be deregulated in cancer cells. Therefore, homeostatic regulation of these important cellular signaling pathways by isoflavones could be useful for the activation of cell death signaling, which could result in the induction of apoptosis of both pre-cancerous and/or cancerous cells without affecting normal cells. In this article, we have attempted to summarize the current state-of-our-knowledge regarding the induction of cancer cell death pathways by isoflavones, which is believed to be mediated through the regulation of multiple cellular signaling pathways. The knowledge gained from this article will provide a comprehensive view on the molecular mechanism(s) by which soy isoflavones may exert their effects on the prevention of tumor progression and/or treatment of human malignancies, which would also aid in stimulating further in-depth mechanistic research and foster the initiation of novel clinical trials.
Highlights
Cancer cells are known to exhibit deregulations in multiple signaling pathways, leading to uncontrolled cell proliferation and acquired anti-apoptosis features
We found that isoflavone-induced inhibition of cell proliferation and induction of apoptosis are partly mediated through the regulation of the Akt/FOXO3a/GSK-3β/androgen receptor (AR) signaling network [94]
The data from in vivo human and animal studies and in vitro experiments clearly suggest that isoflavone exerts its inhibitory effects on carcinogenesis and cancer progression by induction of apoptosis and inhibition of cell proliferation
Summary
Cancer cells are known to exhibit deregulations in multiple signaling pathways, leading to uncontrolled cell proliferation and acquired anti-apoptosis features. The activated endonuclease selectively cleaves DNA at sites located between nucleosomal units, generating typical ~180–200 bp × n DNA fragments with histone and eventually leading to changes in the morphological features [11] These features include chromatin aggregation, nuclear and cytoplasmic condensation, partition of cytoplasm and nucleus into membrane bound-vesicles that are known as apoptotic bodies. Experimental studies have demonstrated that these dietary compounds can enhance the anti-tumor activity of chemotherapeutic agents by regulation of cellular signal transduction pathways, resulting in the induction of apoptotic cell death Among these compounds, isoflavones show their strong effects on apoptosis pathways. Emerging evidence from increasing number of investigations on isoflavones has shown that isoflavones exert their pleiotropic effects on cancer cells through targeting multiple cellular signaling pathways including NF-κB, Akt, MAPK, Wnt, Notch, p53, and AR pathways, suggesting that isoflavone could be useful either alone or in combination with conventional therapeutics for the prevention of tumor progression and/or treatment of human malignancies
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