Oral trivalent bismuth ions decrease, and trivalent indium or ruthenium ions increase, intestinal tumor burden in ApcΔ14/+ mice

Abstract

Immature forms of the peptide hormone gastrin have been implicated in the development of colorectal cancer (CRC). The biological activity of glycine-extended gastrin (Ggly) is dependent on the binding of Fe³⁺ ions in vitro and in vivo. The aim of the present study was to determine the effect of blocking Fe³⁺ ion binding to Ggly, using Bi³⁺, In³⁺ or Ru³⁺ ions, on the development of intestinal tumors in APC^Δ14/+ mice. APC^Δ14/+ mice were treated orally with Bi³⁺, In³⁺ or Ru³⁺ ions for up to 60 days, serum trace metals were analyzed by inductively coupled plasma mass spectrometry, and the incidence and size of intestinal tumors were assessed. Bi³⁺ treatment significantly decreased the number of tumors larger than 3 mm in male mice. In³⁺ or Ru³⁺ treatment significantly increased the tumor burden in all animals and In³⁺ increased the number of tumors larger than 3 mm or 5 mm in male mice alone. The fact that binding of In³⁺ or Ru³⁺ ions to Ggly was orders of magnitude stronger than the binding of Bi³⁺ ions implies that the inhibitory effect of Bi³⁺ ions is not a consequence of a reduction in Ggly activity. However, further testing of higher doses of Bi³⁺ ions for longer periods as an oral treatment for intestinal tumors is warranted.