Mangoni Monica, Sottili Mariangela, Gerini Chiara, Desideri Isacco, Bastida Cinzia, Pallotta Stefania, Castiglione Francesca, Bonomo Pierluigi, Meattini Icro, Greto Daniela, Olmetto Emanuela, Terziani Francesca, Becherini Carlotta, Delli Paoli Camilla, Trombetta Laura, Loi Mauro, Biti Giampaolo, Livi Lorenzo
Radiotherapy Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Largo Brambilla 3, 50134 Firenze, Italy.
Radiotherapy Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Largo Brambilla 3, 50134 Firenze, Italy.
Oral Oncol. 2017 Jan;64:52-58. doi: 10.1016/j.oraloncology.2016.11.018. Epub 2016 Dec 3.
Due to its anti-inflammatory, antifibrotic and antineoplastic properties, the PPAR gamma agonist rosiglitazone is of interest in prevention and therapy of radiation-induced toxicities. We aimed to evaluate the radioprotective effect of rosiglitazone in a mouse model of radiation-induced oral mucositis.
Oral mucositis was obtained by irradiation of the oral region of C57BL/6J mice, pretreated or not with rosiglitazone. Mucositis was assessed by macroscopic scoring, histology and molecular analysis. Tumor xenograft was obtained by s.c. injection of Hep-2 cells in CD1 mice. Tumor volume was measured twice a week to evaluate effect of rosiglitazone alone and combined with radiotherapy.
Irradiated mice showed typical features of oral mucositis, such as oedema and reddening, reaching the peak of damage after 12-15days. Rosiglitazone markedly reduced visible signs of mucositis and significantly reduced the peak. Histological analysis showed the presence of an inflammatory cell infiltrate after irradiation; the association with rosiglitazone noticeably reduced infiltration. Rosiglitazone significantly inhibited radiation-induced tnfα, Il-6 and Il-1β gene expression. Rosiglitazone controlled the increase of TGF-β and NF-kB p65 subunit proteins induced by irradiation, and enhanced the expression of catalase. Irradiation and rosiglitazone significantly reduced tumor volume as compared to control. Rosiglitazone did not protect tumor from the therapeutic effect of radiation.
Rosiglitazone exerted a protective action on normal tissues in radiation-induced mucositis. Moreover, it showed antineoplastic properties on head-neck carcinoma xenograft model and selective protection of normal tissues. Thus, PPAR gamma agonists should be further investigated as radioprotective agents in head and neck cancer.
由于具有抗炎、抗纤维化和抗肿瘤特性，过氧化物酶体增殖物激活受体γ（PPARγ）激动剂罗格列酮在预防和治疗辐射诱导的毒性方面受到关注。我们旨在评估罗格列酮在辐射诱导的口腔黏膜炎小鼠模型中的辐射防护作用。
通过对C57BL/6J小鼠口腔区域进行照射来诱导口腔黏膜炎，小鼠分为罗格列酮预处理组和非预处理组。通过宏观评分、组织学和分子分析评估黏膜炎情况。通过在CD1小鼠皮下注射Hep-2细胞获得肿瘤异种移植模型。每周测量两次肿瘤体积，以评估罗格列酮单独使用及与放疗联合使用的效果。
照射后的小鼠表现出典型的口腔黏膜炎特征，如水肿和发红，在12 - 15天后损伤达到峰值。罗格列酮显著减轻了黏膜炎的可见症状，并显著降低了峰值。组织学分析显示照射后存在炎性细胞浸润；与罗格列酮联合使用可明显减少浸润。罗格列酮显著抑制辐射诱导的肿瘤坏死因子α（TNFα）、白细胞介素6（IL-6）和白细胞介素1β（IL-1β）基因表达。罗格列酮可控制辐射诱导的转化生长因子β（TGF-β）和核因子κB p65亚基蛋白的增加，并增强过氧化氢酶的表达。与对照组相比，照射和罗格列酮显著降低了肿瘤体积。罗格列酮并未使肿瘤免受辐射的治疗作用。
罗格列酮对辐射诱导的黏膜炎中的正常组织具有保护作用。此外，它对头颈部癌异种移植模型显示出抗肿瘤特性，并对正常组织具有选择性保护作用。因此，PPARγ激动剂应作为头颈癌的辐射防护剂进行进一步研究。
