Afatinib radiosensitizes head and neck squamous cell carcinoma cells by targeting cancer stem cells
| Autor: | Norifumi Nakamura, Toshiro Kibe, Shosei Kishida, Michiko Kishida, William M. Lydiatt, Russell B. Smith, Maneesh Jain, Chi Lin, Rahat Jahan, Shuo Wang, Satyanarayana Rachagani, Sicong Li, Suprit Gupta, Surinder K. Batra, Apar Kishor Ganti, Asif Khurshid Qazi, Vivek Verma, Anery Patel, Muzafar A. Macha, Dwight T. Jones, Parthasarathy Seshacharyulu |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Oncology Radiation-Sensitizing Agents medicine.medical_specialty Radiosensitizer Pathology Afatinib Population afatinib Mice Nude Apoptosis Radiation Tolerance head and neck squamous cell carcinoma (HNSCC) Mice 03 medical and health sciences 0302 clinical medicine Cancer stem cell Internal medicine Biomarkers Tumor Tumor Cells Cultured medicine Animals Humans Epidermal growth factor receptor education Cell Proliferation education.field_of_study biology business.industry Cancer medicine.disease Xenograft Model Antitumor Assays Head and neck squamous-cell carcinoma 3. Good health ErbB Receptors 030104 developmental biology Head and Neck Neoplasms 030220 oncology & carcinogenesis Carcinoma Squamous Cell Neoplastic Stem Cells Quinazolines biology.protein Erlotinib radiosensitization business Research Paper medicine.drug |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Muzafar A. Macha 1, 2 , Satyanarayana Rachagani 2 , Asif Khurshid Qazi 2 , Rahat Jahan 2 , Suprit Gupta 2 , Anery Patel 3 , Parthasarathy Seshacharyulu 2 , Chi Lin 4 , Sicong Li 4 , Shuo Wang 4 , Vivek Verma 4 , Shosei Kishida 5 , Michiko Kishida 5 , Norifumi Nakamura 6 , Toshiro Kibe 6 , William M. Lydiatt 1 , Russell B. Smith 1 , Apar K. Ganti 3, 7 , Dwight T. Jones 1 , Surinder K. Batra 2, 8, 9 , Maneesh Jain 2, 8 1 Department of Otolaryngology/Head and Neck Surgery, University of Nebraska Medical Center, Omaha, NE 68198, USA 2 Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA 3 Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA 4 Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE 68198, USA 5 Department of Biochemistry and Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan 6 Department of Oral and Maxillofacial Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan 7 VA Nebraska Western Iowa Health Care System and University of Nebraska Medical Center, Omaha, NE 68198, USA 8 Buffett Cancer Center, Omaha, NE 68198, USA 9 Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA Correspondence to: Muzafar A. Macha, email: muzafar.macha@unmc.edu Keywords: head and neck squamous cell carcinoma (HNSCC), afatinib, radiosensitization Received: November 02, 2016 Accepted: February 06, 2017 Published: February 18, 2017 ABSTRACT The dismal prognosis of locally advanced and metastatic squamous cell carcinoma of the head and neck (HNSCC) is primarily due to the development of resistance to chemoradiation therapy (CRT). Deregulation of Epidermal Growth Factor Receptor (EGFR) signaling is involved in HNSCC pathogenesis by regulating cell survival, cancer stem cells (CSCs), and resistance to CRT. Here we investigated the radiosensitizing activity of the pan-EGFR inhibitor afatinib in HNSCC in vitro and in vivo . Our results showed strong antiproliferative effects of afatinib in HNSCC SCC1 and SCC10B cells, compared to immortalized normal oral epithelial cells MOE1a and MOE1b. Comparative analysis revealed stronger antitumor effects with afatinib than observed with erlotinib. Furthermore, afatinib enhanced in vitro radiosensitivity of SCC1 and SCC10B cells by inducing mesenchymal to epithelial transition, G1 cell cycle arrest, and the attenuating ionizing radiation (IR)-induced activation of DNA double strand break repair (DSB) ATM/ATR/CHK2/BRCA1 pathway. Our studies also revealed the effect of afatinib on tumor sphere- and colony-forming capabilities of cancer stem cells (CSCs), and decreased IR-induced CSC population in SCC1 and SCC10B cells. Furthermore, we observed that a combination of afatinib with IR significantly reduced SCC1 xenograft tumors (median weight of 168.25 ± 20.85 mg; p = 0.05) compared to afatinib (280.07 ± 20.54 mg) or IR alone (324.91 ± 28.08 mg). Immunohistochemical analysis of SCC1 tumor xenografts demonstrated downregulation of the expression of IR-induced pEGFR1, ALDH1 and upregulation of phosphorylated γH2AX by afatinib. Overall, afatinib reduces tumorigenicity and radiosensitizes HNSCC cells. It holds promise for future clinical development as a novel radiosensitizer by improving CSC eradication. |
| Databáze: | OpenAIRE |
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