Inhibitory effect of dicationic diphenylfurans on production of type I collagen by human fibroblasts and activated hepatic stellate cells.
Excessive production of extracellular matrix is responsible for clinical manifestations of fibroproliferative disorders and drugs which can inhibit excessive synthesis of type I collagen are needed for the therapy. Several dicationic diphenylfurans were synthesized and were found to bind RNA. Two of these type compounds were able to reduce synthesis of type I collagen by human fibroblasts and human activated hepatic stellate cells (HSCs). Activated HSCs are responsible for collagen production in liver fibrosis. When added at 40 microM compound 588 reduced intracellular level and secretion of procollagen alpha1(I) by 50%, while compound 654 reduced these parameters by more than 80% at 20 microM. 654 also significantly reduced secretion of fibronectin. Toxic effects were observed at 80 microM for 588 and 40 microM for 654. 654 reduced expression of a reporter gene with collagen signal peptide, while expression of the same gene without signal peptide was unaffected. Also, expression of intracellular proteins tubulin and calnexin was unchanged. 654 accumulated inside the cell in the cytoplasm and did not change the steady-state level of collagen mRNAs. Treatment of cells with proteosome inhibitor MG132 did not change the inhibitory effect of 654, suggesting that 654 acts as suppressor of translation of proteins containing a signal peptide. Most secreted proteins of fibroblasts and activated HSCs are components of extracellular matrix. Therefore inhibition of their production, as shown here for procollagen alpha1(I) and fibronectin, may be a useful property of some of diphenylfurans, making these compounds a basis for development of antifibrotic drugs.
Stefanovic
Lela
L
Department of Biomedical Science, Florida State University College of Medicine, Tallahassee, FL 32306, USA.
Stephens
Chad E
CE
Boykin
David
D
Stefanovic
Branko
B
D001550:Benzamidines / Q000494:pharmacology*; D002461:Cell Line, Transformed; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005663:Furans / Q000494:pharmacology*; D006801:Humans; D007728:Kupffer Cells / Q000187:drug effects* / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D011347:Procollagen; D012333:RNA, Messenger / Q000378:metabolism
D001550:Benzamidines; D024042:Collagen Type I; D005353:Fibronectins; D005663:Furans; D007976:Leupeptins; D011347:Procollagen; D012333:RNA, Messenger; C033286:furamidine; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde