Abstract
Ferric chelates may be used as oral iron supplements or phosphate binders but both ferric citrate and ferric EDTA have been shown to promote tumor burden in murine models of colon cancer. Here we studied their effects on cancer cell growth, at typical supplemental iron levels encountered in the gastrointestinal tract (0.01-0.2 mM). Caco-2 and/or Hutu-80 cells were exposed to these forms of chelated iron or to ferrous sulfate and outcomes were assessed using cell proliferation assays, proteome profiler arrays, western blot, and ELISA. Ferric EDTA and ferric citrate increased cellular levels of the onco-protein amphiregulin and its receptor (EGFr) which in turn stimulated the activation of the MAP kinase ERK. Simultaneously, the expression of the negative Wnt regulator, DKK-1, increased suggesting that cell proliferation through the Wnt pathway may be less pronounced in the presence of ferric EDTA and ferric citrate, unlike for ferrous sulfate. Moreover, ferrous sulfate did not increase levels of cellular amphiregulin or EGFr. We conclude that specific iron compounds affect cell signaling differently and some may increase the risk of colon cancer advancement in an amphiregulin-dependent fashion. Further scrutiny of safe oral iron use is merited.
Highlights
Different chemical forms of oral iron are widely used in the prevention and treatment of iron deficiency anemia [1] and some may be used as ‘phosphate binders’ to control dietary phosphate absorption in patients with renal disease [2, 3]
Amphiregulin is induced in response to ferric citrate and ferric Ethylenediaminetetraacetic acid (EDTA)
Targeted antibody arrays were used to detect cancer-related protein levels on pooled triplicates of Caco-2 or Hutu-80 cells incubated with high concentrations (0.5-2 mM) of ferric citrate, which approximates to an equivalent 150-600 mg oral iron dose in a human subject as might be used for dietary phosphate binding in renal patients [3]
Summary
Different chemical forms of oral iron are widely used in the prevention and treatment of iron deficiency anemia [1] and some may be used as ‘phosphate binders’ to control dietary phosphate absorption in patients with renal disease [2, 3]. Certain of these, notably two different ferric iron chelates, ferric EDTA and ferric citrate, have been observed to promote colon cancer in mice [4,5,6,7]. Oral administration of ferric EDTA drove ulcerative colitis-associated carcinogenesis in two murine models, namely DSS-induced colitis and interleukin-2 knockouts. These findings were in contrast to low-dose intraperitoneal injections of iron-dextran (6 or 12 mg/kg body weight) which did not significantly affect tumor incidence or number, indicating that it is not body iron status per se that exacerbates colon cancer growth. The obvious conclusion for the differential effects of oral and parenteral iron is that oral iron temporarily accumulates in the colon, where transit times are relatively slow, and if it is bioavailable, this may promote local cancer growth, oxidative stress, and DNA damage [8]
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