Plant Polyphenols: Cancer Therapeutics through Modulation of miRNA Functions
Bioactive compounds that are found in plants are referred to as phytochemicals. Some of the most beneficial plant-derived phytochemicals are the phenolic compounds. Phenolic compounds are so called because their chemical structure is composed of one or more aromatic carbon rings containing one or more hydroxyl groups. Plant phenolic compounds exhibit potent anti-oxidant activities and chemopreventive properties (i.e. antimutagenic and anticarcinogenic) as well as being able to interfere with tumor promotion and progression. The anticancer properties of plants should not seem surprising given that numerous studies have shown that a diet high in fruits, vegetables, and whole grains is strongly associated with a reduced risk of cancer. The National Institutes of Health (NIH) has identified at least 40 edible plants that possess cancer preventive properties. Within the realm of Chinese herbal medicine there are over 400 species of plants and herbs that are associated with cancer prevention.
There are literally hundreds of phenolic compounds that have been identified or tested for medicinal benefit. These compounds include non-flavonoid phenolic acids and phenolic acid analogs, stilbenes, curcuminoids, coumarins, lignans, tannins, quinones, and the flavonoids. The physiological and pharmacological functions associated with plant-derived phenolic compounds likely are related to their antioxidant and free radical scavenging properties. The more –OH groups present in a given compound the more antioxidant is the compound.
There are literally hundreds of phenolic compounds that have been identified or tested for medicinal benefit. These compounds include non-flavonoid phenolic acids and phenolic acid analogs, stilbenes, curcuminoids, coumarins, lignans, tannins, quinones, and the flavonoids. The physiological and pharmacological functions associated with plant-derived phenolic compounds likely are related to their antioxidant and free radical scavenging properties. The more –OH groups present in a given compound the more antioxidant is the compound.
I recently wrote a brief post discussing a certain class of small non-coding RNAs called microRNAs (miRNAs) as a background, principally, to be able to open this discussion of the potential therapeutic benefits of plant-derived phenolic compounds exerted via modulation of the activities and functions of miRNAs:
Some of the most well documented anticancer effects of plant-derived phenols have been demonstrated for curcumin (prevalent in turmeric), resveratrol (prevalent in red grapes), quercetin (prevalent in soy beans), epigallocatechin-3-gallate (EGCG; prevalent in green tea leaves), hesperidin (prevalent in citrus fruits), and genistein (prevalent in fava beans). Each of theses phenols have been shown to exert a portion of their anticancer effects by regulating different miRNAs which are implicated in certain types of cancer.
Several recent review papers have documented the numerous clinical trials and research studies that have been carried out recently demonstrating a tight correlation between consumption of plant-derived phenolic compounds and reduction in cancer progression as well as increased survival rates:
Targeting miRNAs by Polyphenols: Novel Therapeutic Strategy for Cancer
microRNAs as New Targets of Dietary Polyphenols
The scope of the involvement of plant-derived phenolic compounds as therapeutic agents in diseases such as cancer is well beyond the scope of this blob post, however, I will highlight and summarize a few of the studies:
Curcumin has been consumed around the world for thousand (if not millions) of years. Curcumin is predominantly found in the Indian spice turmeric (Curcuma longa). Curcumin inhibits the invasion and metastatic properties of colon cancer cells by targeting the oncogenic miRNA identified as miR-21. Curcumin exerts this effect by blocking the binding of a transcription factor to the promoter region of the miR-21 gene. miR-21 normally inhibits the expression of a tumor suppressor gene (a gene whose encoded product represses the ability of cancers to develop) such that reduced miR-21 expression as a result of curcumin consumption results in enhanced expression of the tumor suppressor gene whose normal function is to inhibit the progression of certain cancers. In addition, by inhibiting miR-21 expression, curcumin promotes the death (apoptosis: programmed cell death) of certain types of cancer cells.
Targeting miRNAs by Polyphenols: Novel Therapeutic Strategy for Cancer
microRNAs as New Targets of Dietary Polyphenols
The scope of the involvement of plant-derived phenolic compounds as therapeutic agents in diseases such as cancer is well beyond the scope of this blob post, however, I will highlight and summarize a few of the studies:
Curcumin has been consumed around the world for thousand (if not millions) of years. Curcumin is predominantly found in the Indian spice turmeric (Curcuma longa). Curcumin inhibits the invasion and metastatic properties of colon cancer cells by targeting the oncogenic miRNA identified as miR-21. Curcumin exerts this effect by blocking the binding of a transcription factor to the promoter region of the miR-21 gene. miR-21 normally inhibits the expression of a tumor suppressor gene (a gene whose encoded product represses the ability of cancers to develop) such that reduced miR-21 expression as a result of curcumin consumption results in enhanced expression of the tumor suppressor gene whose normal function is to inhibit the progression of certain cancers. In addition, by inhibiting miR-21 expression, curcumin promotes the death (apoptosis: programmed cell death) of certain types of cancer cells.
Resveratrol is another important polyphenol that is most widely known for its association as a component of red wines. Resveratrol possesses a wide range positive biological activities including an anticancer activity against various cancers. Resveratrol has been shown to modulate the initiation of cancer, the promotion of cancer, and the progression of cancer. Like curcumin, a portion of the anticancer effects of resveratrol are exerted through the regulation of the oncogenic expression of miR-21.
Although there are several oncogenic miRNAs, the expression of at least three have been shown to modulated by genistein. Overexpression of miR-1260b has been shown to be associated with renal (kidney) cancers and treatment of renal cancer cells in culture demonstrated that genistein contributed to reduced expression of miR-1260b and, subsequently, the level of miR-1260b target mRNAs remained unchanged. Genistein has also been shown, in cell culture assays, to reduce the level of expression of miR021 and another oncogenic miRNA, miR-95.
In animal models of cancer quercetin has also been shown to reduced the level of oncogenic miR-21 expression. In addition, quercetin treatment of cancer cells in culture resulted in significant reductions in the production of reactive oxygen species (ROS) such as super oxide anion.
At the other end of the spectrum there are numerous studies that have shown that plant-derived phenolic compounds can lead to increased expression of tumor suppressor miRNAs. For example, the treatment of human melanoma (skin cancer) cells with green tea EGCG resulted in increased expression of miRNA genes of the let-7 family. Increased let-7 gene family genes is associated with impairment of tumor development. In addition to EGCG, quercetin and resveratrol have also been shown to increase let-7 gene expression.
The take home message: for many years anecdotal and hard-core clinical data have conclusively demonstrated that diets enriched in vegetables and fruits prevent disease and increase the potential for life extension. In recent years the underlying biochemical processes modulated by plant-derived compounds has begun to be elucidated. This understanding will result in increased access to therapeutic regimens for diseases, such as cancer, that may involve the simple modulation of ones dietary intake.
Although there are several oncogenic miRNAs, the expression of at least three have been shown to modulated by genistein. Overexpression of miR-1260b has been shown to be associated with renal (kidney) cancers and treatment of renal cancer cells in culture demonstrated that genistein contributed to reduced expression of miR-1260b and, subsequently, the level of miR-1260b target mRNAs remained unchanged. Genistein has also been shown, in cell culture assays, to reduce the level of expression of miR021 and another oncogenic miRNA, miR-95.
In animal models of cancer quercetin has also been shown to reduced the level of oncogenic miR-21 expression. In addition, quercetin treatment of cancer cells in culture resulted in significant reductions in the production of reactive oxygen species (ROS) such as super oxide anion.
At the other end of the spectrum there are numerous studies that have shown that plant-derived phenolic compounds can lead to increased expression of tumor suppressor miRNAs. For example, the treatment of human melanoma (skin cancer) cells with green tea EGCG resulted in increased expression of miRNA genes of the let-7 family. Increased let-7 gene family genes is associated with impairment of tumor development. In addition to EGCG, quercetin and resveratrol have also been shown to increase let-7 gene expression.
The take home message: for many years anecdotal and hard-core clinical data have conclusively demonstrated that diets enriched in vegetables and fruits prevent disease and increase the potential for life extension. In recent years the underlying biochemical processes modulated by plant-derived compounds has begun to be elucidated. This understanding will result in increased access to therapeutic regimens for diseases, such as cancer, that may involve the simple modulation of ones dietary intake.
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