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Inhibition of DNA-PK by gefitinib causes synergism between gefitinib and cisplatin in NSCLC

Lung cancer has the highest incidence and mortality rates among the malignant tumor types world-wide. Platinum-based chemotherapy is the main treatment for advanced non-small-cell lung cancer (NSCLC), and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have greatly improved t...

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Autores principales: Pan, Chi, Duan, Huijie, Wu, Yinan, Zhu, Chunpeng, Yi, Chenghao, Duan, Yin, Lu, Demin, Guo, Cheng, Wu, Deqi, Wang, Yanyan, Fu, Xianhua, Xu, Jing, Chen, Yiding, Luo, Meng, Tian, Wei, Pan, Tao, Xu, Wenhong, Zhang, Suzhan, Huang, Jianjin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473755/
https://www.ncbi.nlm.nih.gov/pubmed/32945394
http://dx.doi.org/10.3892/ijo.2020.5103
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author Pan, Chi
Duan, Huijie
Wu, Yinan
Zhu, Chunpeng
Yi, Chenghao
Duan, Yin
Lu, Demin
Guo, Cheng
Wu, Deqi
Wang, Yanyan
Fu, Xianhua
Xu, Jing
Chen, Yiding
Luo, Meng
Tian, Wei
Pan, Tao
Xu, Wenhong
Zhang, Suzhan
Huang, Jianjin
author_facet Pan, Chi
Duan, Huijie
Wu, Yinan
Zhu, Chunpeng
Yi, Chenghao
Duan, Yin
Lu, Demin
Guo, Cheng
Wu, Deqi
Wang, Yanyan
Fu, Xianhua
Xu, Jing
Chen, Yiding
Luo, Meng
Tian, Wei
Pan, Tao
Xu, Wenhong
Zhang, Suzhan
Huang, Jianjin
author_sort Pan, Chi
collection PubMed
description Lung cancer has the highest incidence and mortality rates among the malignant tumor types world-wide. Platinum-based chemotherapy is the main treatment for advanced non-small-cell lung cancer (NSCLC), and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have greatly improved the survival of patients with EGFR-sensitive mutations. However, there is no standard therapy for treating patients who are EGFR-TKI resistant. Combining EGFR-TKIs and platinum-based chemotherapy is the most popular strategy in the clinical practice. However, the synergistic mechanism between EGFR-TKIs and platinum remains unknown. Therefore, the aim of the present study was to determine the synergistic mechanism of gefitinib (an EGFR-TKI) and cisplatin (a main platinum-based drug). MTT assay, apoptosis analysis, tumorsphere formation and an orthotropic xenograft mouse model were used to examine the combination effects of gefitinib and cisplatin on NSCLC. Co-immunoprecipitation and immunofluorescence were used to identify the underlying mechanism. It was found that gefi-tinib could selectively inhibit EGFR from entering the nucleus, decrease DNA-PK activity and enhance the cytotoxicity of cisplatin on NSCLC. Collectively, the results suggested that inhibition of DNA-dependent protein kinase by gefitinib may be due to the synergistic mechanism between gefitinib and cisplatin. Thus, the present study provides a novel insight into potential biomarkers for the selection of combination therapy of gefitinib and cisplatin.
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spelling pubmed-74737552020-09-13 Inhibition of DNA-PK by gefitinib causes synergism between gefitinib and cisplatin in NSCLC Pan, Chi Duan, Huijie Wu, Yinan Zhu, Chunpeng Yi, Chenghao Duan, Yin Lu, Demin Guo, Cheng Wu, Deqi Wang, Yanyan Fu, Xianhua Xu, Jing Chen, Yiding Luo, Meng Tian, Wei Pan, Tao Xu, Wenhong Zhang, Suzhan Huang, Jianjin Int J Oncol Articles Lung cancer has the highest incidence and mortality rates among the malignant tumor types world-wide. Platinum-based chemotherapy is the main treatment for advanced non-small-cell lung cancer (NSCLC), and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have greatly improved the survival of patients with EGFR-sensitive mutations. However, there is no standard therapy for treating patients who are EGFR-TKI resistant. Combining EGFR-TKIs and platinum-based chemotherapy is the most popular strategy in the clinical practice. However, the synergistic mechanism between EGFR-TKIs and platinum remains unknown. Therefore, the aim of the present study was to determine the synergistic mechanism of gefitinib (an EGFR-TKI) and cisplatin (a main platinum-based drug). MTT assay, apoptosis analysis, tumorsphere formation and an orthotropic xenograft mouse model were used to examine the combination effects of gefitinib and cisplatin on NSCLC. Co-immunoprecipitation and immunofluorescence were used to identify the underlying mechanism. It was found that gefi-tinib could selectively inhibit EGFR from entering the nucleus, decrease DNA-PK activity and enhance the cytotoxicity of cisplatin on NSCLC. Collectively, the results suggested that inhibition of DNA-dependent protein kinase by gefitinib may be due to the synergistic mechanism between gefitinib and cisplatin. Thus, the present study provides a novel insight into potential biomarkers for the selection of combination therapy of gefitinib and cisplatin. D.A. Spandidos 2020-07-27 /pmc/articles/PMC7473755/ /pubmed/32945394 http://dx.doi.org/10.3892/ijo.2020.5103 Text en Copyright: © Pan et al. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Articles
Pan, Chi
Duan, Huijie
Wu, Yinan
Zhu, Chunpeng
Yi, Chenghao
Duan, Yin
Lu, Demin
Guo, Cheng
Wu, Deqi
Wang, Yanyan
Fu, Xianhua
Xu, Jing
Chen, Yiding
Luo, Meng
Tian, Wei
Pan, Tao
Xu, Wenhong
Zhang, Suzhan
Huang, Jianjin
Inhibition of DNA-PK by gefitinib causes synergism between gefitinib and cisplatin in NSCLC
title Inhibition of DNA-PK by gefitinib causes synergism between gefitinib and cisplatin in NSCLC
title_full Inhibition of DNA-PK by gefitinib causes synergism between gefitinib and cisplatin in NSCLC
title_fullStr Inhibition of DNA-PK by gefitinib causes synergism between gefitinib and cisplatin in NSCLC
title_full_unstemmed Inhibition of DNA-PK by gefitinib causes synergism between gefitinib and cisplatin in NSCLC
title_short Inhibition of DNA-PK by gefitinib causes synergism between gefitinib and cisplatin in NSCLC
title_sort inhibition of dna-pk by gefitinib causes synergism between gefitinib and cisplatin in nsclc
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473755/
https://www.ncbi.nlm.nih.gov/pubmed/32945394
http://dx.doi.org/10.3892/ijo.2020.5103
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