title: Uptake of anti-anemic substance ferric-sorbitol-citrate by normal and malignant cells and its effects on expression of transferrin receptor 1 and ferritin.
abstract: Iron-containing antianemic drug ferric-sorbitol-citrate (FSC) inhibits the proliferation of various cancer cell lines in vitro and causes a regression of experimental murine tumors in vivo but does not affect the proliferation of nonmalignant cells. Growth modification caused by FSC iron involves a diminished expression of Bcl-2 and an overexpression of p53 proto-oncogene, accompanied by an increased incidence of apoptosis. Aiming to evaluate further the activity principle of the anticancer effects of this antianemic drug, in this study, we analyzed the utilization of iron from FSC and the effects of FSC iron on transferrin receptor 1 (TfR1) and ferritin expression. Without FSC iron, all the cell lines had an equal expression of TfR1, but if cultured in FSC-supplemented medium, human colon SW620 and laryngeal carcinoma Hep cells exhibited a lower expression of TfR1-positive cells than nonmalignant Wi38 fibroblasts and pancreatic carcinoma MiaPaCa2 cells. The most sensitive to FSC iron were colon carcinoma SW620 cells, whereas Wi38 fibroblasts were not sensitive at all. Increased iron uptake by colon carcinoma cells was noticed in the first 3 hours of the incubation with FSC iron, whereas higher FSC iron concentrations and longer incubation also impaired ferritin expression in SW260 colon carcinoma cells. Thus, the anticancer ability of FSC could result from its higher initial utilization of iron and consecutive negative signal for the expression of TfR1 in tumor cells. Tumor cells containing lower amounts of ferritin are probably more sensitive to oxidative stress caused by iron overload, whereas FSC iron itself was proven to be chemically stable and did not induce lipid peroxidation.
authors.affiliation: University of Zagreb, Medical School, Zagreb, Croatia.
authors.forename: Maja
authors.initials: M
authors.lastname: Prutki
authors.forename: Marija
authors.initials: M
authors.lastname: Poljak-Blazi
authors.forename: Branka
authors.initials: B
authors.lastname: Mihaljevic
authors.forename: Visnja
authors.initials: V
authors.lastname: Orescanin
authors.forename: Neven
authors.initials: N
authors.lastname: Zarkovic
mesh_terms: D000740:Anemia; D015703:Antigens, CD / Q000378:metabolism*; D002460:Cell Line; D002951:Citrates / Q000494:pharmacology*; D003470:Culture Media; D005290:Ferric Compounds / Q000494:pharmacology*; D005293:Ferritins / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D007501:Iron / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008054:Lipid Peroxides / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011990:Receptors, Transferrin / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C068126:CD71 antigen; D002951:Citrates; D003470:Culture Media; D005290:Ferric Compounds; D008054:Lipid Peroxides; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011990:Receptors, Transferrin; C421458:ferric-sorbitol-citrate; D005293:Ferritins; D007501:Iron