Involvement of lipid peroxidation, oncogene expression and induction of apoptosis in the antitumorous activity of ferric-sorbitol-citrate.
We described before that iron-containing, anti-anaemic drug, ferric-sorbitol-citrate complex (FSC) inhibited proliferation of various murine cancer cells in vitro and caused tumour regression in vivo, but did not affect proliferation of the non-malignant cells. The aim of this study was to evaluate further the anticancer activity mechanism of FSC using human colon cancer cell line CaCo2. After treatment with FSC for 72 hours impaired proliferative ability and viability of CaCo2 cells as observed. Growth modification caused by FSC involved diminished expression of Bcl-2, and over-expression of mp53 proto-oncogenes, accompanied by increased incidence of apoptosis. Immunostaining the cells applying monoclonal antibodies for lipid peroxidation product 4-hydroxynonenal (HNE) showed that FSC-iron increased intracellular HNE, but did not induce severe HNE-mediated oxidative stress. Thus, antitumorous mechanism of FSC involves modulation of oncogene expression and induction of apoptosis apparently not triggered by lipid peroxidation-mediated oxidative stress, although FSC might restore endogenous HNE production in the CaCo2 cells to level resembling physiological for various non-malignant cells and tissues. Higher dose of FSC increased also number of intracellular ferritin positive CaCo2 cells.
Poljak-Blazi
M
M
Rudjer Bosković Institute, Dept. of Molecular Medicine, Zagreb, Croatia.
Kralj
M
M
Hadzija
M P
MP
Zarković
N
N
Zarković
K
K
Waeg
G
G
D000447:Aldehydes / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D018938:Caco-2 Cells; D019343:Citric Acid / Q000494:pharmacology*; D004338:Drug Combinations; D005290:Ferric Compounds / Q000494:pharmacology*; D016158:Genes, p53; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D011519:Proto-Oncogenes; D013012:Sorbitol / Q000494:pharmacology*
D000447:Aldehydes; D000970:Antineoplastic Agents; D004338:Drug Combinations; D005290:Ferric Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; C008170:citric acid, iron, sorbitol drug combination; D019343:Citric Acid; D013012:Sorbitol; C027576:4-hydroxy-2-nonenal