Mangoni Monica, Sottili Mariangela, Gerini Chiara, Desideri Isacco, Bastida Cinzia, Pallotta Stefania, Castiglione Francesca, Bonomo Pierluigi, Meattini Icro, Greto Daniela, Cappelli Sabrina, Di Brina Lucia, Loi Mauro, Biti Giampaolo, Livi Lorenzo
Radiotherapy Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Firenze, Italy.
Medical Physic Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Firenze, Italy.
United European Gastroenterol J. 2017 Mar;5(2):218-226. doi: 10.1177/2050640616640443. Epub 2016 Jul 8.
Because of its anti-inflammatory, anti-fibrotic, anti-apoptotic and anti-neoplastic properties, the PPAR-γ agonist rosiglitazone is an interesting drug for investigating for 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.
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.
Rosiglitazone markedly reduced histological 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 , , and at 24 hours and at 72 hours post-irradiation. Rosiglitazone reduced HT-29 clonogenic survival, but only produced a slight reduction of xenograft tumour growth.
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.
由于过氧化物酶体增殖物激活受体γ（PPAR-γ）激动剂罗格列酮具有抗炎、抗纤维化、抗凋亡和抗肿瘤特性，它是一种用于研究预防和治疗辐射诱导肠道损伤的有趣药物。我们旨在评估罗格列酮在急性肠道损伤小鼠模型中的辐射防护作用，评估辐射防护是否对正常组织具有选择性，还是也发生在肿瘤细胞中。
对小鼠进行全身照射（12 Gy），照射时给予或不给予罗格列酮（5 mg/kg/天）。照射后24小时和72小时，处死小鼠并收集空肠。对HT-29人结肠癌细胞进行单次2（1000个细胞）、4（1500个细胞）或6（2000个细胞）Gy照射，照射前1小时给予或不给予罗格列酮（20 μM）。对移植了HT-29细胞的CD1小鼠进行照射（16 Gy），照射时给予或不给予罗格列酮；测量肿瘤体积33天。
罗格列酮显著减轻了肠道结构改变的组织学迹象，即绒毛缩短、黏膜下增厚、隐窝坏死改变、水肿、凋亡以及照射诱导的炎性浸润。罗格列酮在照射后24小时和72小时显著降低了磷酸化核因子κB p65（p-NF-κB p65）的磷酸化水平和转化生长因子β（TGFβ）蛋白表达，在照射后24小时显著降低了 、 、 和 的基因表达，在照射后72小时显著降低了 的基因表达。罗格列酮降低了HT-29细胞的克隆存活率，但仅轻微降低了异种移植肿瘤的生长。
罗格列酮对正常组织具有保护作用，并在辐射诱导的肠道毒性模型中减少肠道结构改变和炎症，而不干扰辐射对HT-29癌细胞的作用。PPAR-γ激动剂在腹部和盆腔放疗中的应用应进一步研究。
