Impaired Proliferation and DNA Synthesis of a Human Tumor Cell Line (HELA) Caused by Short Treatment with the Antianemic Drug Jectofer (Ferric-Sorbitol-Citrate) and the Lipid Peroxidation Product 4-Hydroxynonenal

Abstract

Anti-anaemic drug, ferric-sorbitol-citrate complex (FSC), inhibit tumour cell growth through the mechanisms which are complex and not entirely understood. The probable mechanisms of described effects of iron is iron-induced oxidative stress of the treated cells. Hence, the effects of FSC on HeLa cell growth in vitro were compared with the biological activity of one of the major mediators of the oxygen free radicals--aldehyde 4-hydroxinonenal (HNE), to see if the effects of FSC and of HNE resemble each other. Impaired proliferative ability and DNA synthesis of HeLa cells was observed after treatment with anti-anaemic drug FSC for 24 hours. After treatment with FSC and culturing of HeLa cells in fresh medium for 24 or 96 hours the cells did not proliferate at all, DNA synthesis was transiently recovered and then diminished again. HNE blocked cell proliferation during the time the aldehyde was present in culture and 24 h later. Afterwards, the cells proliferated as control non-treated cells. HNE did not inhibit DNA synthesis during treatment, but intensity of 3H-thymidine incorporation was lower after preincubation. Thus, both FSC and HNE interfere with the basic mechanisms of the cell growth regulation, while antitumour activity of FSC resembles, but does not necessarily include iron induced lipid peroxidation.

Catalytic function of Drosophila melanogaster glutathione S‐transferase DmGSTS1‐1 (GST‐2) in conjugation of lipid peroxidation end products

“…The resulting functional modifications of key cellular proteins have been well documented [64,67,68]. Particularly striking among the many physiological effects of 4‐HNE is the modulation of the cell cycle [69–71], differentiation [72–74], and apoptosis [73,75,76]. It is intriguing to speculate that 4‐HNE may act as a signal during embryogenesis and tissue remodeling when the above processes are prominent.…”

Uptake of Anti-Anemic Substance Ferric-Sorbitol-Citrate by Normal and Malignant Cells and Its Effects on Expression of Transferrin Receptor 1 and Ferritin

“…5,6 As we have previously shown, iron in the form of ferric-sorbitol-citrate (FCS) (Jectofer; Astra, Linz, Austria) inhibited the proliferation of CaCo2 (colon carcinoma), Hep2 (laryngeal carcinoma), MiaPaCa2 (pancreatic carcinoma), and HeLa (cervix carcinoma) cell lines but did not affect the proliferation of the nonmalignant fibroblast cell line HEF522 and human bone marrow cells. 7,8 FSC also caused a regression of B16 mouse melanoma in vitro and in vivo. 9 An increased number of cells in G1 and in early Sphase suggested that iron excess blocked the cell cycle before the onset of DNA synthesis.…”

“…Final concentrations of the FSC iron were from 10 Ϫ5 to 10 Ϫ3 M. These concentration ranges were chosen on the basis of previous experience with the ability of FSC iron to modify tumor cell growth in vitro. 7,8…”

“…7 Malignant SW620 colon carcinoma cells were at two orders of magnitude more sensitive to this cytotoxic effect of FSC iron than nonmalignant Wi38 fibroblasts, because they have the very same pattern of reaction to the FSC iron treatment as was observed for colon carcinoma cells, even if treated with 10 Ϫ4 or 10 Ϫ5 M FSC iron, whereas fibroblasts exerted cytotoxic effects of FSC iron only if treated with 10 Ϫ3 M iron FSC. [7][8][9] It is not likely that cytotoxicity of FSC iron could result from potential pro-oxidative effects of iron. Namely, FSC iron did not induce the lipid peroxidation of human plasma.…”