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.
Highlights
Natural polyphenols are subject to increasing interest due to their interesting pharmacological activities [1,2,3,4]
This is in agreement with the findings of He et al who observed that the hydroxyl groups at position 4’ and 7 are important for exhibiting inhibitor activity toward PRL-3 [37]
The results indicated that both epimers suppress the activity of PRL-3
Summary
Natural polyphenols are subject to increasing interest due to their interesting pharmacological activities [1,2,3,4]. 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 PLOS ONE | DOI:10.1371/journal.pone.0134336. Chemical Biology Core Facility, and the EMBL Flow Cytometry Core laboratory Less abundant epicatechins contained in green tea are PLOS ONE | DOI:10.1371/journal.pone.0134336 July 30, 2015
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