Selective inhibition of cell proliferation and DNA synthesis by the polysulphated carbohydrate l-carrageenan.
l-Carrageenan is a polysulphated carbohydrate that antagonises some heparin-binding growth factors. We assessed the effect of l-carrageenan on the proliferation of a panel of cell lines, some of which require heparin-binding growth factors for mitogenesis. The importance of growth factor antagonism for the anti-proliferative activity was also determined. Cell proliferation was determined by cell counts and a tetrazolium dye (MTT) assay, and DNA synthesis was determined by thymidine incorporation. The proliferation of the basic fibroblast growth factor (bFGF)-dependent endothelial cell line FBHE was inhibited by daily administration of l-carrageenan in a dose-dependent manner [concentration inhibiting cell growth by 50% (IC50 value), approx. 0.5 microgram/ml]. However, excess bFGF did not reverse the inhibitory effect. DNA synthesis was completely inhibited by concentrations of l-carrageenan that nonetheless allowed significant protein synthesis to occur. The proliferation of the androgen-dependent prostate-carcinoma cell line LNCaP was also inhibited by l-carrageenan (IC50 value, 5.5 micrograms/ml) and the cells were arrested at the G1/S boundary. l-Carrageenan inhibited DNA synthesis in MCF-7 cells stimulated by bFGF and transforming growth factor alpha (TGF alpha) but not in those stimulated by insulin-like growth factor 1 (IGF-1). Blocking IGF-1-mediated DNA synthesis with anti-IGF-1 receptor antibody alpha IR3 enhanced the inhibitory activity of l-carrageenan against MCF-7 cells grown in serum. A number of other transformed and non-transformed cell lines were either partially inhibited or not inhibited by l-carrageenan. l-Carrageenan had low anti-coagulant activity. l-Carrageenan is a selective anti-proliferative agent and warrants further investigation for anti-angiogenic therapy (in view of its activity against endothelial cells) and for the treatment of androgen-dependent prostate cancer.
Hoffman
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Clinical Oncology and Radiotherapeutics Unit, MRC Centre, Cambridge, UK.
Burns
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D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002351:Carrageenan / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D003864:Depression, Chemical; D004727:Endothelium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D006131:Growth Inhibitors; D016222:Fibroblast Growth Factor 2; D002351:Carrageenan; D004247:DNA