Bismuth ions inhibit the biological activity of non-amidated gastrins in vivo

Kovac, Suzana; Loh, Su-Wen; Lachal, Shamilah; Shulkes, Arthur; Baldwin, Graham S.

doi:10.1016/j.bcp.2011.11.030

Cited by 12 publications

(9 citation statements)

References 33 publications

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“…We also reported previously that bismuth ions inhibit ferric ion binding, and analysis of the binding data with the program BioEqs was consistent with mixed inhibition, in which the gastrin-bismuth complex was still able to bind two ferric ions. [ 11 ] In the present study the binding of a range of other trivalent metal ions to gastrins was investigated by ultraviolet absorption spectroscopy. Both Gamide and Ggly bound Ga 3+ , In 3+ or Ru 3+ ; no binding of other trivalent metal ions from group 8/9 (Os 3+ , Rh 3+ ), group 13 (Al 3+ , Tl 3+ ), or group 15 (As 3+ , Sb 3+ ) was detected (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…Bi 3+ ions, on the other hand, by competing for the ferric ion binding site of Ggly, block biological activity in vitro [ 10 ] and in the normal colorectal mucosa in both mice and rats in vivo . [ 11 ] In contrast, ferric ions were not required for the biological activity of Gamide. [ 12 ] In the present study the binding of several other metal ions to Gamide and Ggly was investigated either via changes in absorption on addition of the metal ion itself, or by alterations in the absorption of the ferric ion-gastrin complex in the presence of the metal ion.…”

Section: Introductionmentioning

confidence: 99%

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High Affinity Binding of Indium and Ruthenium Ions by Gastrins

2015

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The peptide hormone gastrin binds two ferric ions with high affinity, and iron binding is essential for the biological activity of non-amidated forms of the hormone. Since gastrins act as growth factors in gastrointestinal cancers, and as peptides labelled with Ga and In isotopes are increasingly used for cancer diagnosis, the ability of gastrins to bind other metal ions was investigated systematically by absorption spectroscopy. The coordination structures of the complexes were characterized by extended X-ray absorption fine structure (EXAFS) spectroscopy. Changes in the absorption of gastrin in the presence of increasing concentrations of Ga3+ were fitted by a 2 site model with dissociation constants (Kd) of 3.3 x 10−7 and 1.1 x 10−6 M. Although the absorption of gastrin did not change upon the addition of In3+ ions, the changes in absorbance on Fe3+ ion binding in the presence of indium ions were fitted by a 2 site model with Kd values for In3+ of 6.5 x 10−15 and 1.7 x 10−7 M. Similar results were obtained with Ru3+ ions, although the Kd values for Ru3+ of 2.6 x 10−13 and 1.2 x 10−5 M were slightly larger than observed for In3+. The structures determined by EXAFS all had metal:gastrin stoichiometries of 2:1 but, while the metal ions in the Fe, Ga and In complexes were bridged by a carboxylate and an oxygen with a metal-metal separation of 3.0–3.3 Å, the Ru complex clearly demonstrated a short range Ru—Ru separation, which was significantly shorter, at 2.4 Å, indicative of a metal-metal bond. We conclude that gastrin selectively binds two In3+ or Ru3+ ions, and that the affinity of the first site for In3+ or Ru3+ ions is higher than for ferric ions. Some of the metal ion-gastrin complexes may be useful for cancer diagnosis and therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

High Affinity Binding of Indium and Ruthenium Ions by Gastrins

2015

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“…On the other hand, there is now abundant evidence that Fe 3+ ions are essential for the biological activity of non-amidated gastrins such as progastrin and Ggly [14,16,17]. However the identity of the receptors for non-amidated gastrins is still controversial [21][22][23], and the use of 111 In-Ggly, 106 Ru-Ggly or 68 Ga-Ggly complexes may help to resolve that debate.…”

Section: Discussionmentioning

confidence: 99%

“…Gamide and Ggly both bind two ferric ions [13], the first to Glu7 and the second to Glu8 and Glu9 [14,15]. The biological activity of Ggly as a stimulant of cell proliferation and migration is dependent on the presence of ferric ions, and thus can be completely blocked either by the substitution Glu7Ala, by competition with bismuth ions, or by treatment with the iron chelator desferrioxamine (DFO) [14], [16,17]. In contrast, ferric ions are not required for the activation of the CCK2R by Gamide, as the resultant biological activity is unaffected by the substitution Glu7Ala or by treatment with DFO [18].…”

Section: Introductionmentioning

confidence: 99%

Complexes of gastrin with In3+, Ru3+ or Ga3+ ions are not recognised by the cholecystokinin 2 receptor

et al. 2017

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The peptide hormone gastrin (Gamide) binds trivalent metal ions, including indium (In), ruthenium (Ru) and gallium (Ga), with high affinity. Complexes of gastrin with chelated isotopes of In and Ga have previously been used for the location of tumours expressing the cholecystokinin 2 receptor (CCK2R). The aim of the present study was to purify the complexes of Gamide with radioactive isotopes of In, Ru or Ga and to investigate their ability to bind to the CCK2R. The radioactive Gamide complexes were purified on Sep-Pak C18 cartridges or by anion exchange HPLC. Binding to the CCK2R was assessed with a stably transfected clone of the gastric carcinoma cell line AGS. The Ru-Gamide complex could be eluted from the C18 cartridge; theIn-Gamide and Ga-Gamide complexes bound irreversibly. All three complexes were successfully purified by anion exchange HPLC. The failure to detect binding of theIn-Gamide, Ru-Gamide andGa-Gamide complexes to the CCK2R suggests that formation of these complexes will not be useful for the detection of tumours expressing this receptor, but may instead provide alternative ways to block the actions of Gamide as a growth factor or a stimulant of gastric acid secretion. The complexes between the hormone gastrin and radioactive In,Ru or Ga ions were purified by anion exchange HPLC using a NaCl gradient. The failure to detect binding of the complexes to the cholecystokinin 2 receptor suggests that metal ion treatment may provide novel approaches to block the biological actions of gastrin.

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“…182 By contrast, progastrin and Ggly have little direct effect on gastric acidity but potentiate the effects of Gamide on acid secretion. 185 Together with its safe dosing, antioxidant and mucosal healing qualities, bismuth is a good candidate as an allround gastrointestinal protective agent. Such nonamidated gastrins may also act as growth factors in colorectal cancer.…”

Section: Bismuthmentioning

confidence: 99%