Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland. Veterans Administration Maryland Health Care System, Baltimore, Maryland; Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland; Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland; Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland.
Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic bladder disorder with epithelial thinning or ulceration, pain, urinary frequency and urgency, for which there is no reliably effective therapy. We previously reported that IC/PBS bladder epithelial cells make a glycopeptide antiproliferative factor or "APF" (Neu5Acα2-3Galβ1-3GalNAcα-O-TVPAAVVVA) that induces abnormalities in normal cells similar to those in IC/PBS cells in vitro, including decreased proliferation, decreased tight junction formation, and increased paracellular permeability. We screened inactive APF derivatives for their ability to block antiproliferative activity of asialylated-APF ("as-APF") in normal bladder cells, and determined the ability of as-APF-blocking derivatives to normalize tight junction protein expression, paracellular permeability, and/or proliferation of IC/PBS cells. Only two of these derivatives [Galβ1-3GalNAcα-O-TV-(D-pipecolic acid)-AAVVVA and Galβ1-3GalNAcα-O-TV-(D-proline)-AAVVVA] blocked as-APF antiproliferative activity in normal cells (p< .001 for both). Both of these antagonists also 1) significantly increased mRNA expression of ZO-1, occludin, and claudins 1, 4, 8, and 12 in IC/PBS cells by qRT-PCR; 2) normalized IC/PBS epithelial cell tight junction protein expression and tight junction formation by confocal immunofluorescence microscopy; and 3) decreased paracellular permeability of (14) C-mannitol and (3) H-inulin between confluent IC/PBS epithelial cells on Transwell plates, suggesting that these potent APF antagonists may be useful for development as IC/PBS therapies.
Keay S, Kaczmarek P, Zhang CO, Koch K, Szekely Z, Barchi JJ Jr, Michejda C. Are you the author?
Reference: Chem Biol Drug Des. 2011 Feb 26. Epub ahead of print.