BERKELEY, CA (UroToday.com) -
IC/BPS is characterized by increased bladder epithelial thinning/ulceration and permeability, for which there is currently no reliably effective therapy. The novel strategy of inhibiting a toxin (antiproliferative factor) produced uniquely by bladder cells in IC/BPS as therapy for this disorder has not yet been employed. This is what Susan Keay and associates from Baltimore and Frederick Maryland explored in a recent publication.
She had previously determined that IC/BPS bladder epithelial cells produce a small frizzled 8 protein-related factor (APF) that inhibits proliferation and regulates bladder epithelial cell gene expression resulting in a less proliferative cell phenotype. To date, over 40 synthetic APF derivatives have been tested for their ability to inhibit normal bladder epithelial cell proliferation. Thirty-two of these were found to be completely inactive in cell proliferation assays. The authors preincubated primary normal bladder cells with each of the 32 inactive APF derivatives prior to incubation with active synthetic APF to determine their ability to block APF activity. Only D-proline as-APF and D-pipecolic acid as-APF were able to significantly attenuate the active synthetic APF antiproliferative activity .
Thus, the authors present evidence that two synthetic APF derivatives block APF’s inhibitory effects on cell proliferation in both synthetic APF-treated primary normal bladder epithelial cells and bladder epithelial cells explanted from IC/BPS patients. They also show that synthetic APF treatment of normal bladder epithelial cells in vitro can cause changes in mRNA and protein expression of claudin 1,4,8 and 12 similar to those seen in IC/BPS cells. Expression of these tight junction proteins plus ZO-1 and occludin, is also normalized by treatment with either APF antagonist glycopeptide in vitro. They conclude that these findings suggest that these molecules may be useful for development as IC/BPS therapies.
Keay S, Kaczmarek P, Zhang CO, Koch K, Szekely Z, Barchi JJ Jr, Michejda C
Chem Biol Drug Des. 2011 Jun;77(6):421-30
10.1111/j.1747-0285.2011.01108.x
PubMed Abstract
PMID: 21352500
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