Cicek Betul, Hacimuftuoglu Ahmet, Kuzucu Mehmet, Cetin Ahmet, Yeni Yesim, Genc Sidika, Yildirim Serkan, Bolat Ismail, Kantarci Mecit, Gul Mustafa, Hayme Serhat, Matthaios Dimitris, Vageli Dimitra P, Doukas Sotirios G, Tsatsakis Aristidis, Taghizadehghalehjoughi Ali
Faculty of Medicine, Department of Physiology, Erzincan Binali Yildirim University, Erzincan 24100, Turkey.
Faculty of Medicine, Department of Medical Pharmacology, Ataturk University, Erzurum 25240, Turkey.
Pharmaceuticals (Basel). 2023 Feb 1;16(2):221. doi: 10.3390/ph16020221.
According to population-based studies, lung cancer is the prominent reason for cancer-related mortality worldwide in males and is also rising in females at an alarming rate. Sorafenib (SOR), which is approved for the treatment of hepatocellular carcinoma and renal cell carcinoma, is a multitargeted protein kinase inhibitor. Additionally, SOR is the subject of interest for preclinical and clinical trials in lung cancer. This study was designed to assess in vivo the possible effects of sorafenib (SOR) in diethylnitrosamine (DEN)-induced lung carcinogenesis and examine its probable mechanisms of action. A total of 30 adult male rats were divided into three groups (1) control, (2) DEN, and (3) DEN + SOR. The chemical induction of lung carcinogenesis was performed by injection of DEN intraperitoneally at 150 mg/kg once a week for two weeks. The DEN-administered rats were co-treated with SOR of 10 mg/kg by oral gavage for 42 alternate days. Serum and lung tissue samples were analyzed to determine SRY-box transcription factor 2 (SOX-2) levels. The tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) levels were measured in lung tissue supernatants. Lung sections were analyzed for cyclooxygenase-2 (COX-2) and c-Jun N-terminal kinase (JNK) histopathologically. In addition, cyclooxygenase-2 (COX-2) and c-Jun N-terminal kinase (JNK) were analyzed by immunohistochemistry and immunofluorescence methods, respectively. SOR reduced the level of SOX-2 that maintenance of cancer stemness and tumorigenicity, and TNF-α and IL-1β levels. Histopathological analysis demonstrated widespread inflammatory cell infiltration, disorganized alveolar structure, hyperemia in the vessels, and thickened alveolar walls in DEN-induced rats. The damage was markedly reduced upon SOR treatment. Further, immunohistochemical and immunofluorescence analysis also revealed increased expression of COX-2 and JNK expression in DEN-intoxicated rats. However, SOR treatment alleviated the expression of these inflammatory markers in DEN-induced lung carcinogenesis. These findings suggested that SOR inhibits DEN-induced lung precancerous lesions through decreased inflammation with concomitant in reduced SOX-2 levels, which enables the maintenance of cancer stem cell properties.
基于人群的研究表明，肺癌是全球男性癌症相关死亡的主要原因，在女性中也以惊人的速度上升。索拉非尼（SOR）是一种多靶点蛋白激酶抑制剂，已被批准用于治疗肝细胞癌和肾细胞癌。此外，SOR是肺癌临床前和临床试验的研究对象。本研究旨在评估索拉非尼（SOR）在二乙基亚硝胺（DEN）诱导的肺癌发生中的体内可能作用，并研究其可能的作用机制。总共30只成年雄性大鼠被分为三组：（1）对照组，（2）DEN组，（3）DEN + SOR组。通过每周一次腹腔注射150 mg/kg的DEN，持续两周来进行肺癌发生的化学诱导。给接受DEN的大鼠通过口服灌胃给予10 mg/kg的SOR，隔天一次，共42天。分析血清和肺组织样本以确定SRY盒转录因子2（SOX-2）水平。在肺组织上清液中测量肿瘤坏死因子α（TNF-α）和白细胞介素-1β（IL-1β）水平。对肺切片进行环氧化酶-2（COX-2）和c-Jun氨基末端激酶（JNK）的组织病理学分析。此外，分别通过免疫组织化学和免疫荧光方法分析环氧化酶-2（COX-2）和c-Jun氨基末端激酶（JNK）。SOR降低了维持癌症干性和致瘤性的SOX-2水平以及TNF-α和IL-1β水平。组织病理学分析表明，DEN诱导的大鼠存在广泛的炎性细胞浸润、肺泡结构紊乱、血管充血和肺泡壁增厚。SOR治疗后损伤明显减轻。此外，免疫组织化学和免疫荧光分析还显示，DEN中毒大鼠中COX-2和JNK表达增加。然而，SOR治疗减轻了DEN诱导的肺癌发生中这些炎症标志物的表达。这些发现表明，SOR通过减少炎症并同时降低SOX-2水平来抑制DEN诱导的肺癌前病变，而SOX-2水平的降低有助于维持癌症干细胞特性。
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