Objective: Because of its antiinflammatory, antifibrotic, antiapoptotic and antineoplastic properties, the PPAR-γ agonist rosiglitazone is an interesting drug for investigating its use in the prevention and treatment of radiation-induced intestinal damage. We aimed to evaluate the radioprotective effect of rosiglitazone in a murine model of acute intestinal damage, assessing whether radioprotection is selective for normal tissues or also occurs in tumour cells. Methods: Mice were total-body irradiated (12 Gy), with or without rosiglitazone (5 mg/kg/day). After 24 and 72 hours, mice were sacrificed and the jejunum was collected. HT-29 human colon cancer cells were irradiated with a single dose of 2 (1000 cells), 4 (1500 cells) or 6 (2000 cells) Gy, with or without adding rosiglitazone (20 μM) 1 hour before irradiation. HT-29-xenografted CD1 mice were irradiated (16 Gy) with or without rosiglitazone; tumour volumes were measured for 33 days. Results: Rosiglitazone markedly reduced histologic signs of altered bowel structures, that is, villi shortening, submucosal thickening, necrotic changes in crypts, oedema, apoptosis, and inflammatory infiltrate induced by irradiation. Rosiglitazone significantly decreased p-NF-kB p65 phosphorylation and TGFβ protein expression at 24 and 72 hours post-irradiation and significantly decreased gene expression of Collagen1, Mmp13, Tnfα, Bax at 24 hours and p53 at 72 hours post-irradiation. Rosiglitazone reduced HT-29 clonogenic survival, but only produced a slight reduction of xenograft tumour growth. Conclusion: Rosiglitazone exerts a protective effect on normal tissues and reduces alterations in bowel structures and inflammation in a radiation-induced bowel toxicity model, without interfering with the radiation effect on HT-29 cancer cells. PPAR-γ agonists should be further investigated for their application in abdominal and pelvic irradiation.

A PPAR-gamma agonist protects from radiation-induced intestinal toxicity / Mangoni, M; Sottili, M; Gerini, C; Desideri, I; Bastida, C; Pallotta, S; Castiglione, F; Bonomo, P; Meattini, I; Greto, D; Cappelli, S; Di Brina, L; Loi, M; Biti, G; Livi, L.. - In: UNITED EUROPEAN GASTROENTEROLOGY JOURNAL. - ISSN 2050-6406. - STAMPA. - 5:(2017), pp. 218-226. [10.1177/2050640616640443]

A PPAR-gamma agonist protects from radiation-induced intestinal toxicity

MANGONI, MONICA;SOTTILI, MARIANGELA;GERINI, CHIARA;DESIDERI, ISACCO;BASTIDA, CINZIA;PALLOTTA, STEFANIA;CASTIGLIONE, FRANCESCA;BONOMO, PIERLUIGI;MEATTINI, ICRO;GRETO, DANIELA;LOI, MAURO;BITI, GIAMPAOLO;LIVI, LORENZO
2017

Abstract

Objective: Because of its antiinflammatory, antifibrotic, antiapoptotic and antineoplastic properties, the PPAR-γ agonist rosiglitazone is an interesting drug for investigating its use in the prevention and treatment of radiation-induced intestinal damage. We aimed to evaluate the radioprotective effect of rosiglitazone in a murine model of acute intestinal damage, assessing whether radioprotection is selective for normal tissues or also occurs in tumour cells. Methods: Mice were total-body irradiated (12 Gy), with or without rosiglitazone (5 mg/kg/day). After 24 and 72 hours, mice were sacrificed and the jejunum was collected. HT-29 human colon cancer cells were irradiated with a single dose of 2 (1000 cells), 4 (1500 cells) or 6 (2000 cells) Gy, with or without adding rosiglitazone (20 μM) 1 hour before irradiation. HT-29-xenografted CD1 mice were irradiated (16 Gy) with or without rosiglitazone; tumour volumes were measured for 33 days. Results: Rosiglitazone markedly reduced histologic signs of altered bowel structures, that is, villi shortening, submucosal thickening, necrotic changes in crypts, oedema, apoptosis, and inflammatory infiltrate induced by irradiation. Rosiglitazone significantly decreased p-NF-kB p65 phosphorylation and TGFβ protein expression at 24 and 72 hours post-irradiation and significantly decreased gene expression of Collagen1, Mmp13, Tnfα, Bax at 24 hours and p53 at 72 hours post-irradiation. Rosiglitazone reduced HT-29 clonogenic survival, but only produced a slight reduction of xenograft tumour growth. Conclusion: Rosiglitazone exerts a protective effect on normal tissues and reduces alterations in bowel structures and inflammation in a radiation-induced bowel toxicity model, without interfering with the radiation effect on HT-29 cancer cells. PPAR-γ agonists should be further investigated for their application in abdominal and pelvic irradiation.
2017
5
218
226
Mangoni, M; Sottili, M; Gerini, C; Desideri, I; Bastida, C; Pallotta, S; Castiglione, F; Bonomo, P; Meattini, I; Greto, D; Cappelli, S; Di Brina, L; L...espandi
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1052863
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