Sorafenib Alleviates Inflammatory Signaling of Tumor Microenvironment in Precancerous Lung Injuries
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...
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| Format: | Article |
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MDPI AG
2023-02-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/16/2/221 |
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| author | Betul Cicek Ahmet Hacimuftuoglu Mehmet Kuzucu Ahmet Cetin Yesim Yeni Sidika Genc Serkan Yildirim Ismail Bolat Mecit Kantarci Mustafa Gul Serhat Hayme Dimitris Matthaios Dimitra P. Vageli Sotirios G. Doukas Aristidis Tsatsakis Ali Taghizadehghalehjoughi |
| author_facet | Betul Cicek Ahmet Hacimuftuoglu Mehmet Kuzucu Ahmet Cetin Yesim Yeni Sidika Genc Serkan Yildirim Ismail Bolat Mecit Kantarci Mustafa Gul Serhat Hayme Dimitris Matthaios Dimitra P. Vageli Sotirios G. Doukas Aristidis Tsatsakis Ali Taghizadehghalehjoughi |
| author_sort | Betul Cicek |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T08:17:50Z |
| format | Article |
| id | doaj.art-5d2db7db747c40c694202d7eed0ee5c4 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-11T08:17:50Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-5d2db7db747c40c694202d7eed0ee5c42023-11-16T22:36:40ZengMDPI AGPharmaceuticals1424-82472023-02-0116222110.3390/ph16020221Sorafenib Alleviates Inflammatory Signaling of Tumor Microenvironment in Precancerous Lung InjuriesBetul Cicek0Ahmet Hacimuftuoglu1Mehmet Kuzucu2Ahmet Cetin3Yesim Yeni4Sidika Genc5Serkan Yildirim6Ismail Bolat7Mecit Kantarci8Mustafa Gul9Serhat Hayme10Dimitris Matthaios11Dimitra P. Vageli12Sotirios G. Doukas13Aristidis Tsatsakis14Ali Taghizadehghalehjoughi15Faculty of Medicine, Department of Physiology, Erzincan Binali Yildirim University, Erzincan 24100, TurkeyFaculty of Medicine, Department of Medical Pharmacology, Ataturk University, Erzurum 25240, TurkeyFaculty of Arts and Sciences, Department of Biology, Erzincan Binali Yildirim University, Erzincan 24100, TurkeyDepartment of Biology, Graduate School of Natural and Applied Sciences, Erzincan Binali Yildirim University, 24100 Erzincan, TurkeyFaculty of Medicine, Department of Medical Pharmacology, Malatya Turgut Ozal University, Malatya 44210, TurkeyFaculty of Medicine, Department of Medical Pharmacology, Bilecik Seyh Edebali University, Bilecik 11230, TurkeyFaculty of Veterinary, Department of Pathology, Ataturk University, Erzurum 25240, TurkeyFaculty of Veterinary, Department of Pathology, Ataturk University, Erzurum 25240, TurkeyFaculty of Medicine, Department of Radiology, Erzincan Binali Yildirim University, Erzincan 24100, TurkeyFaculty of Medicine, Department of Physiology, Ataturk University, Erzurum 25240, TurkeyFaculty of Medicine, Department of Biostatistics, Erzincan Binali Yildirim University, Erzincan 24100, TurkeyOncology Department, General Hospital of Rhodos, 85100 Rhodos, GreeceYale Larynx Laboratory, Department of Surgery (Otololaryngology), Yale School of Medicine, Yale University, New Havan, CT 06510, USADepartment of Internal Medicine, Division of Gastroenterology, Rutgers/Saint Peter’s University Hospital, New Brunswick, NJ 08901, USADepartment of Forensic Sciences and Toxicology, Faculty of Medicine, University of Crete, 71003 Heraklion, GreeceFaculty of Medicine, Department of Medical Pharmacology, Bilecik Seyh Edebali University, Bilecik 11230, TurkeyAccording 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.https://www.mdpi.com/1424-8247/16/2/221lung carcinogenesisdiethylnitrosamineinflammationSOX-2COX-2JNK |
| spellingShingle | Betul Cicek Ahmet Hacimuftuoglu Mehmet Kuzucu Ahmet Cetin Yesim Yeni Sidika Genc Serkan Yildirim Ismail Bolat Mecit Kantarci Mustafa Gul Serhat Hayme Dimitris Matthaios Dimitra P. Vageli Sotirios G. Doukas Aristidis Tsatsakis Ali Taghizadehghalehjoughi Sorafenib Alleviates Inflammatory Signaling of Tumor Microenvironment in Precancerous Lung Injuries Pharmaceuticals lung carcinogenesis diethylnitrosamine inflammation SOX-2 COX-2 JNK |
| title | Sorafenib Alleviates Inflammatory Signaling of Tumor Microenvironment in Precancerous Lung Injuries |
| title_full | Sorafenib Alleviates Inflammatory Signaling of Tumor Microenvironment in Precancerous Lung Injuries |
| title_fullStr | Sorafenib Alleviates Inflammatory Signaling of Tumor Microenvironment in Precancerous Lung Injuries |
| title_full_unstemmed | Sorafenib Alleviates Inflammatory Signaling of Tumor Microenvironment in Precancerous Lung Injuries |
| title_short | Sorafenib Alleviates Inflammatory Signaling of Tumor Microenvironment in Precancerous Lung Injuries |
| title_sort | sorafenib alleviates inflammatory signaling of tumor microenvironment in precancerous lung injuries |
| topic | lung carcinogenesis diethylnitrosamine inflammation SOX-2 COX-2 JNK |
| url | https://www.mdpi.com/1424-8247/16/2/221 |
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