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Molecular Mechanisms and Therapeutic Effects of (-)-Epicatechin and Other Polyphenols in Cancer, Inflammation, Diabetes, and Neurodegeneration.

Shay J, Elbaz HA, Lee I, Zielske SP, Malek MH, Hüttemann M - Oxid Med Cell Longev (2015)

Bottom Line: This paper reviews the biological effects of a group of natural compounds called polyphenols, including apigenin, epigallocatechin gallate, genistein, and (-)-epicatechin, with a focus on the latter. (-)-Epicatechin has several unique features responsible for a variety of its effects.One of these is its ability to interact with and neutralize reactive oxygen species (ROS) in the cell. (-)-Epicatechin also modulates cell signaling including the MAP kinase pathway, which is involved in cell proliferation.This paper discusses the potential of some phenolic compounds to maintain, protect, and possibly reinstate health.

View Article: PubMed Central - PubMed

Affiliation: Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA ; Karmanos Cancer Institute, Detroit, MI 48201, USA.

ABSTRACT
With recent insight into the mechanisms involved in diseases, such as cardiovascular disease, cancer, stroke, neurodegenerative diseases, and diabetes, more efficient modes of treatment are now being assessed. Traditional medicine including the use of natural products is widely practiced around the world, assuming that certain natural products contain the healing properties that may in fact have a preventative role in many of the diseases plaguing the human population. This paper reviews the biological effects of a group of natural compounds called polyphenols, including apigenin, epigallocatechin gallate, genistein, and (-)-epicatechin, with a focus on the latter. (-)-Epicatechin has several unique features responsible for a variety of its effects. One of these is its ability to interact with and neutralize reactive oxygen species (ROS) in the cell. (-)-Epicatechin also modulates cell signaling including the MAP kinase pathway, which is involved in cell proliferation. Mutations in this pathway are often associated with malignancies, and the use of (-)-epicatechin holds promise as a preventative agent and as an adjunct for chemotherapy and radiation therapy to improve outcome. This paper discusses the potential of some phenolic compounds to maintain, protect, and possibly reinstate health.

No MeSH data available.


Related in: MedlinePlus

Proposed model of the interference of (−)-epicatechin with cancer signaling, metabolism, and proliferation. (−)-Epicatechin stimulates mitochondrial respiration and biogenesis, thus interfering with Warburg metabolism. At the cell signaling level, the compound inhibits Erk signaling, which interferes with other signaling pathways including EGFR that are known to be hyperactive in cancer. (−)-Epicatechin through Erk and/or other signaling pathways leads to an activation of mitochondrial oxidative phosphorylation, which interferes with Warburg metabolism. Other targets that are inhibited by (−)-epicatechin in cancer cells are NF-κB, Akt, and histone acetyltransferases (HATs). As a result, (−)-epicatechin interferes with cancer signaling, thus rendering the cells more susceptible to apoptosis, an effect that could be utilized to sensitize cancer cells to radiation treatment or chemotherapy. It should be noted that (−)-epicatechin exerts a distinct protective response in noncancerous normal tissue (not shown). This highlights the importance not to generalize the effects but to include detailed information including cell type and treatment regimen.
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fig2: Proposed model of the interference of (−)-epicatechin with cancer signaling, metabolism, and proliferation. (−)-Epicatechin stimulates mitochondrial respiration and biogenesis, thus interfering with Warburg metabolism. At the cell signaling level, the compound inhibits Erk signaling, which interferes with other signaling pathways including EGFR that are known to be hyperactive in cancer. (−)-Epicatechin through Erk and/or other signaling pathways leads to an activation of mitochondrial oxidative phosphorylation, which interferes with Warburg metabolism. Other targets that are inhibited by (−)-epicatechin in cancer cells are NF-κB, Akt, and histone acetyltransferases (HATs). As a result, (−)-epicatechin interferes with cancer signaling, thus rendering the cells more susceptible to apoptosis, an effect that could be utilized to sensitize cancer cells to radiation treatment or chemotherapy. It should be noted that (−)-epicatechin exerts a distinct protective response in noncancerous normal tissue (not shown). This highlights the importance not to generalize the effects but to include detailed information including cell type and treatment regimen.

Mentions: Inflammation has been linked to cancer development, progression, invasion, and metastasis [52] and the use of anti-inflammatory agents has been proposed as an attractive adjunct therapy for the clinic in the future [53], and we here propose that application of (−)-epicatechin may be such a viable approach. In addition to its anti-inflammatory effect several studies concluded a potential for (−)-epicatechin as a novel anticancer drug mediated through additional mechanisms (Figure 2). (−)-Epicatechin was shown to cause DNA damage and apoptosis in acute myeloid leukemia cells in rats when administered orally at a dose of 40 mg/kg body weight for 22 consecutive days [54]. Additionally, (−)-epicatechin was shown to inhibit the proliferation of Hodgkin's lymphoma cells and Jurkat T cells, which was attributed to the ability of (−)-epicatechin to inhibit the binding of NF-κB to DNA in these cells [55] (Figure 2). Interestingly, these effects were not associated with (−)-epicatechin's antioxidant activity, nuclear translocation of NF-κB, or p65 phosphorylation. The mechanism by which (−)-epicatechin inhibits NF-κB–DNA binding is still open to investigation. One molecular target of (−)-epicatechin that may in part explain the anticancer activity has been identified. It is the Na+/H+ exchanger, which is strongly inhibited by (−)-epicatechin, and it was proposed that cancer cell plasma membrane fluidity and cytosolic pH are disturbed, thus interfering with cell proliferation [56, 57].


Molecular Mechanisms and Therapeutic Effects of (-)-Epicatechin and Other Polyphenols in Cancer, Inflammation, Diabetes, and Neurodegeneration.

Shay J, Elbaz HA, Lee I, Zielske SP, Malek MH, Hüttemann M - Oxid Med Cell Longev (2015)

Proposed model of the interference of (−)-epicatechin with cancer signaling, metabolism, and proliferation. (−)-Epicatechin stimulates mitochondrial respiration and biogenesis, thus interfering with Warburg metabolism. At the cell signaling level, the compound inhibits Erk signaling, which interferes with other signaling pathways including EGFR that are known to be hyperactive in cancer. (−)-Epicatechin through Erk and/or other signaling pathways leads to an activation of mitochondrial oxidative phosphorylation, which interferes with Warburg metabolism. Other targets that are inhibited by (−)-epicatechin in cancer cells are NF-κB, Akt, and histone acetyltransferases (HATs). As a result, (−)-epicatechin interferes with cancer signaling, thus rendering the cells more susceptible to apoptosis, an effect that could be utilized to sensitize cancer cells to radiation treatment or chemotherapy. It should be noted that (−)-epicatechin exerts a distinct protective response in noncancerous normal tissue (not shown). This highlights the importance not to generalize the effects but to include detailed information including cell type and treatment regimen.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4477097&req=5

fig2: Proposed model of the interference of (−)-epicatechin with cancer signaling, metabolism, and proliferation. (−)-Epicatechin stimulates mitochondrial respiration and biogenesis, thus interfering with Warburg metabolism. At the cell signaling level, the compound inhibits Erk signaling, which interferes with other signaling pathways including EGFR that are known to be hyperactive in cancer. (−)-Epicatechin through Erk and/or other signaling pathways leads to an activation of mitochondrial oxidative phosphorylation, which interferes with Warburg metabolism. Other targets that are inhibited by (−)-epicatechin in cancer cells are NF-κB, Akt, and histone acetyltransferases (HATs). As a result, (−)-epicatechin interferes with cancer signaling, thus rendering the cells more susceptible to apoptosis, an effect that could be utilized to sensitize cancer cells to radiation treatment or chemotherapy. It should be noted that (−)-epicatechin exerts a distinct protective response in noncancerous normal tissue (not shown). This highlights the importance not to generalize the effects but to include detailed information including cell type and treatment regimen.
Mentions: Inflammation has been linked to cancer development, progression, invasion, and metastasis [52] and the use of anti-inflammatory agents has been proposed as an attractive adjunct therapy for the clinic in the future [53], and we here propose that application of (−)-epicatechin may be such a viable approach. In addition to its anti-inflammatory effect several studies concluded a potential for (−)-epicatechin as a novel anticancer drug mediated through additional mechanisms (Figure 2). (−)-Epicatechin was shown to cause DNA damage and apoptosis in acute myeloid leukemia cells in rats when administered orally at a dose of 40 mg/kg body weight for 22 consecutive days [54]. Additionally, (−)-epicatechin was shown to inhibit the proliferation of Hodgkin's lymphoma cells and Jurkat T cells, which was attributed to the ability of (−)-epicatechin to inhibit the binding of NF-κB to DNA in these cells [55] (Figure 2). Interestingly, these effects were not associated with (−)-epicatechin's antioxidant activity, nuclear translocation of NF-κB, or p65 phosphorylation. The mechanism by which (−)-epicatechin inhibits NF-κB–DNA binding is still open to investigation. One molecular target of (−)-epicatechin that may in part explain the anticancer activity has been identified. It is the Na+/H+ exchanger, which is strongly inhibited by (−)-epicatechin, and it was proposed that cancer cell plasma membrane fluidity and cytosolic pH are disturbed, thus interfering with cell proliferation [56, 57].

Bottom Line: This paper reviews the biological effects of a group of natural compounds called polyphenols, including apigenin, epigallocatechin gallate, genistein, and (-)-epicatechin, with a focus on the latter. (-)-Epicatechin has several unique features responsible for a variety of its effects.One of these is its ability to interact with and neutralize reactive oxygen species (ROS) in the cell. (-)-Epicatechin also modulates cell signaling including the MAP kinase pathway, which is involved in cell proliferation.This paper discusses the potential of some phenolic compounds to maintain, protect, and possibly reinstate health.

View Article: PubMed Central - PubMed

Affiliation: Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA ; Karmanos Cancer Institute, Detroit, MI 48201, USA.

ABSTRACT
With recent insight into the mechanisms involved in diseases, such as cardiovascular disease, cancer, stroke, neurodegenerative diseases, and diabetes, more efficient modes of treatment are now being assessed. Traditional medicine including the use of natural products is widely practiced around the world, assuming that certain natural products contain the healing properties that may in fact have a preventative role in many of the diseases plaguing the human population. This paper reviews the biological effects of a group of natural compounds called polyphenols, including apigenin, epigallocatechin gallate, genistein, and (-)-epicatechin, with a focus on the latter. (-)-Epicatechin has several unique features responsible for a variety of its effects. One of these is its ability to interact with and neutralize reactive oxygen species (ROS) in the cell. (-)-Epicatechin also modulates cell signaling including the MAP kinase pathway, which is involved in cell proliferation. Mutations in this pathway are often associated with malignancies, and the use of (-)-epicatechin holds promise as a preventative agent and as an adjunct for chemotherapy and radiation therapy to improve outcome. This paper discusses the potential of some phenolic compounds to maintain, protect, and possibly reinstate health.

No MeSH data available.


Related in: MedlinePlus