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Procyanidins Negatively Affect the Activity of the Phosphatases of Regenerating Liver.

Stadlbauer S, Rios P, Ohmori K, Suzuki K, Köhn M - PLoS ONE (2015)

Bottom Line: Increasing the number of catechin units in procyanidins to more than three does not further enhance the potency.As PRL overexpression induces cell migration compared to control cells, the effect of procyanidins on this phenotype was studied.Together, our results show that procyanidins negatively affect PRL activity, suggesting that PRLs could be targets in the polypharmacology of natural polyphenols.

View Article: PubMed Central - PubMed

Affiliation: European Molecular Biology Laboratory, Genome Biology Unit, Meyerhofstrasse 1, 69117, Heidelberg, Germany.

ABSTRACT
Natural polyphenols like oligomeric catechins (procyanidins) derived from green tea and herbal medicines are interesting compounds for pharmaceutical research due to their ability to protect against carcinogenesis in animal models. It is nevertheless still unclear how intracellular pathways are modulated by polyphenols. Monomeric polyphenols were shown to affect the activity of some protein phosphatases (PPs). The three phosphatases of regenerating liver (PRLs) are close relatives and promising therapeutic targets in cancer. In the present study we show that several procyanidins inhibit the activity of all three members of the PRL family in the low micromolar range, whereas monomeric epicatechins show weak inhibitory activity. Increasing the number of catechin units in procyanidins to more than three does not further enhance the potency. Remarkably, the tested procyanidins showed selectivity in vitro when compared to other PPs, and over 10-fold selectivity toward PRL-1 over PRL-2 and PRL-3. As PRL overexpression induces cell migration compared to control cells, the effect of procyanidins on this phenotype was studied. Treatment with procyanidin C2 led to a decrease in cell migration of PRL-1- and PRL-3-overexpressing cells, suggesting the compound-dependent inhibition of PRL-promoted cell migration. Treatment with procyanidin B3 led to selective suppression of PRL-1 overexpressing cells, thereby corroborating the selectivity toward PRL-1- over PRL-3 in vitro. Together, our results show that procyanidins negatively affect PRL activity, suggesting that PRLs could be targets in the polypharmacology of natural polyphenols. Furthermore, they are interesting candidates for the development of PRL-1 inhibitors due to their low cellular toxicity and the selectivity within the PRL family.

No MeSH data available.


Related in: MedlinePlus

Structures of catechin-type polyphenols.(A) monomeric polyphenols and (B) oligomeric catechins with B-type (4→8) linkage (procyanidins).
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pone.0134336.g001: Structures of catechin-type polyphenols.(A) monomeric polyphenols and (B) oligomeric catechins with B-type (4→8) linkage (procyanidins).

Mentions: Natural polyphenols are subject to increasing interest due to their interesting pharmacological activities [1–4]. Especially catechin-class polpyhenols (see Fig 1A) such as the green tea polyphenols (–)-epigallocatechin (EGC) and its 3-O-gallate (EGCG) have attracted strong attention due to their health benefits. Less abundant epicatechins contained in green tea are (–)-epicatechin and (–)-epicatechin-3-O-gallate (ECG). Research in the past decade has shown that those tea polyphenols are able to protect against tumor initiation and promotion in animal models [5], however, the understanding of intracellular pathways modulated by these compounds is still incomplete. EGCG, the most abundant green tea polyphenol, was found to induce cell cycle arrest and apoptosis in many cancer cells without affecting normal cells [6]. Their antitumor activity is supposed to be exerted by targeting multiple pathways involved in cancer progression, such as the NF-kappaB, MAPKs, EGFR and IGF-I mediated pathways [7]. More recently it was shown that EGCG functionally antagonizes androgen action at multiple levels in prostate cancer, resulting in inhibition of prostate carcinoma cell growth, thus making it a promising chemotherapeutic agent against hormone-refractory prostate cancer [8].


Procyanidins Negatively Affect the Activity of the Phosphatases of Regenerating Liver.

Stadlbauer S, Rios P, Ohmori K, Suzuki K, Köhn M - PLoS ONE (2015)

Structures of catechin-type polyphenols.(A) monomeric polyphenols and (B) oligomeric catechins with B-type (4→8) linkage (procyanidins).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4520450&req=5

pone.0134336.g001: Structures of catechin-type polyphenols.(A) monomeric polyphenols and (B) oligomeric catechins with B-type (4→8) linkage (procyanidins).
Mentions: Natural polyphenols are subject to increasing interest due to their interesting pharmacological activities [1–4]. Especially catechin-class polpyhenols (see Fig 1A) such as the green tea polyphenols (–)-epigallocatechin (EGC) and its 3-O-gallate (EGCG) have attracted strong attention due to their health benefits. Less abundant epicatechins contained in green tea are (–)-epicatechin and (–)-epicatechin-3-O-gallate (ECG). Research in the past decade has shown that those tea polyphenols are able to protect against tumor initiation and promotion in animal models [5], however, the understanding of intracellular pathways modulated by these compounds is still incomplete. EGCG, the most abundant green tea polyphenol, was found to induce cell cycle arrest and apoptosis in many cancer cells without affecting normal cells [6]. Their antitumor activity is supposed to be exerted by targeting multiple pathways involved in cancer progression, such as the NF-kappaB, MAPKs, EGFR and IGF-I mediated pathways [7]. More recently it was shown that EGCG functionally antagonizes androgen action at multiple levels in prostate cancer, resulting in inhibition of prostate carcinoma cell growth, thus making it a promising chemotherapeutic agent against hormone-refractory prostate cancer [8].

Bottom Line: Increasing the number of catechin units in procyanidins to more than three does not further enhance the potency.As PRL overexpression induces cell migration compared to control cells, the effect of procyanidins on this phenotype was studied.Together, our results show that procyanidins negatively affect PRL activity, suggesting that PRLs could be targets in the polypharmacology of natural polyphenols.

View Article: PubMed Central - PubMed

Affiliation: European Molecular Biology Laboratory, Genome Biology Unit, Meyerhofstrasse 1, 69117, Heidelberg, Germany.

ABSTRACT
Natural polyphenols like oligomeric catechins (procyanidins) derived from green tea and herbal medicines are interesting compounds for pharmaceutical research due to their ability to protect against carcinogenesis in animal models. It is nevertheless still unclear how intracellular pathways are modulated by polyphenols. Monomeric polyphenols were shown to affect the activity of some protein phosphatases (PPs). The three phosphatases of regenerating liver (PRLs) are close relatives and promising therapeutic targets in cancer. In the present study we show that several procyanidins inhibit the activity of all three members of the PRL family in the low micromolar range, whereas monomeric epicatechins show weak inhibitory activity. Increasing the number of catechin units in procyanidins to more than three does not further enhance the potency. Remarkably, the tested procyanidins showed selectivity in vitro when compared to other PPs, and over 10-fold selectivity toward PRL-1 over PRL-2 and PRL-3. As PRL overexpression induces cell migration compared to control cells, the effect of procyanidins on this phenotype was studied. Treatment with procyanidin C2 led to a decrease in cell migration of PRL-1- and PRL-3-overexpressing cells, suggesting the compound-dependent inhibition of PRL-promoted cell migration. Treatment with procyanidin B3 led to selective suppression of PRL-1 overexpressing cells, thereby corroborating the selectivity toward PRL-1- over PRL-3 in vitro. Together, our results show that procyanidins negatively affect PRL activity, suggesting that PRLs could be targets in the polypharmacology of natural polyphenols. Furthermore, they are interesting candidates for the development of PRL-1 inhibitors due to their low cellular toxicity and the selectivity within the PRL family.

No MeSH data available.


Related in: MedlinePlus