Regorafenib induces NOX5-mediated endoplasmic reticulum stress and potentiates the anti-tumor activity of cisplatin in non-small cell lung cancer cells
Lung cancer is one of the most commonly diagnosed cancers worldwide. Although cisplatin-based chemotherapy regimens serve a pivotal role in non-small cell lung cancer (NSCLC) treatment, drug resistance and serious side effects limited its further clinical application. Regorafenib, a small-molecule m...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-05-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558623000222 |
| _version_ | 1797851282430492672 |
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| author | Hehuan Sui Sisi Xiao Suping Jiang Siyuan Wu Haizhen Lin Liyuan Cheng Lihua Ye Qi Zhao Yun Yu Lu Tao Feng-Ming Kong Xiaoying Huang Ri Cui |
| author_facet | Hehuan Sui Sisi Xiao Suping Jiang Siyuan Wu Haizhen Lin Liyuan Cheng Lihua Ye Qi Zhao Yun Yu Lu Tao Feng-Ming Kong Xiaoying Huang Ri Cui |
| author_sort | Hehuan Sui |
| collection | DOAJ |
| description | Lung cancer is one of the most commonly diagnosed cancers worldwide. Although cisplatin-based chemotherapy regimens serve a pivotal role in non-small cell lung cancer (NSCLC) treatment, drug resistance and serious side effects limited its further clinical application. Regorafenib, a small-molecule multi-kinase inhibitor, was demonstrated to have promising anti-tumor activity in various solid tumors. In the present study, we found that regorafenib markedly enhanced cisplatin-induced cytotoxicity in lung cancer cells by activating reactive oxygen species (ROS)-mediated endoplasmic reticulum stress (ER Stress), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) signaling pathways. Regorafenib increased ROS generation by promoting NADPH oxidase 5 (NOX5) expression, and knocking down NOX5 attenuated ROS-mediated cytotoxicity of regorafenib in lung cancer cells. Additionally, mice xenograft model validated that synergistic anti-tumor effects of combined treatment with regorafenib and cisplatin. Our results suggested that combination therapy with regorafenib and cisplatin may serve as a potential therapeutic strategy for some NSCLC patients. |
| first_indexed | 2024-04-09T19:15:25Z |
| format | Article |
| id | doaj.art-1c68055134494322810652d1f1073a18 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 |
| language | English |
| last_indexed | 2024-04-09T19:15:25Z |
| publishDate | 2023-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-1c68055134494322810652d1f1073a182023-04-06T06:10:32ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862023-05-0139100897Regorafenib induces NOX5-mediated endoplasmic reticulum stress and potentiates the anti-tumor activity of cisplatin in non-small cell lung cancer cellsHehuan Sui0Sisi Xiao1Suping Jiang2Siyuan Wu3Haizhen Lin4Liyuan Cheng5Lihua Ye6Qi Zhao7Yun Yu8Lu Tao9Feng-Ming Kong10Xiaoying Huang11Ri Cui12Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Wenzhou University-Wenzhou Medical University Collaborative Innovation Center of Biomedical, Wenzhou, 325035, ChinaCancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Wenzhou University-Wenzhou Medical University Collaborative Innovation Center of Biomedical, Wenzhou, 325035, China; The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, ChinaCancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Wenzhou University-Wenzhou Medical University Collaborative Innovation Center of Biomedical, Wenzhou, 325035, ChinaCancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Wenzhou University-Wenzhou Medical University Collaborative Innovation Center of Biomedical, Wenzhou, 325035, ChinaCancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, ChinaCancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Wenzhou University-Wenzhou Medical University Collaborative Innovation Center of Biomedical, Wenzhou, 325035, ChinaCancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Wenzhou University-Wenzhou Medical University Collaborative Innovation Center of Biomedical, Wenzhou, 325035, ChinaCancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Wenzhou University-Wenzhou Medical University Collaborative Innovation Center of Biomedical, Wenzhou, 325035, ChinaCancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, ChinaCancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, ChinaThe First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Correspondence authors.The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Correspondence authors.Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Wenzhou University-Wenzhou Medical University Collaborative Innovation Center of Biomedical, Wenzhou, 325035, China; Correspondence authors.Lung cancer is one of the most commonly diagnosed cancers worldwide. Although cisplatin-based chemotherapy regimens serve a pivotal role in non-small cell lung cancer (NSCLC) treatment, drug resistance and serious side effects limited its further clinical application. Regorafenib, a small-molecule multi-kinase inhibitor, was demonstrated to have promising anti-tumor activity in various solid tumors. In the present study, we found that regorafenib markedly enhanced cisplatin-induced cytotoxicity in lung cancer cells by activating reactive oxygen species (ROS)-mediated endoplasmic reticulum stress (ER Stress), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) signaling pathways. Regorafenib increased ROS generation by promoting NADPH oxidase 5 (NOX5) expression, and knocking down NOX5 attenuated ROS-mediated cytotoxicity of regorafenib in lung cancer cells. Additionally, mice xenograft model validated that synergistic anti-tumor effects of combined treatment with regorafenib and cisplatin. Our results suggested that combination therapy with regorafenib and cisplatin may serve as a potential therapeutic strategy for some NSCLC patients.http://www.sciencedirect.com/science/article/pii/S1476558623000222NSCLCRegorafenibCisplatinReactive oxygen speciesNOX5 |
| spellingShingle | Hehuan Sui Sisi Xiao Suping Jiang Siyuan Wu Haizhen Lin Liyuan Cheng Lihua Ye Qi Zhao Yun Yu Lu Tao Feng-Ming Kong Xiaoying Huang Ri Cui Regorafenib induces NOX5-mediated endoplasmic reticulum stress and potentiates the anti-tumor activity of cisplatin in non-small cell lung cancer cells Neoplasia: An International Journal for Oncology Research NSCLC Regorafenib Cisplatin Reactive oxygen species NOX5 |
| title | Regorafenib induces NOX5-mediated endoplasmic reticulum stress and potentiates the anti-tumor activity of cisplatin in non-small cell lung cancer cells |
| title_full | Regorafenib induces NOX5-mediated endoplasmic reticulum stress and potentiates the anti-tumor activity of cisplatin in non-small cell lung cancer cells |
| title_fullStr | Regorafenib induces NOX5-mediated endoplasmic reticulum stress and potentiates the anti-tumor activity of cisplatin in non-small cell lung cancer cells |
| title_full_unstemmed | Regorafenib induces NOX5-mediated endoplasmic reticulum stress and potentiates the anti-tumor activity of cisplatin in non-small cell lung cancer cells |
| title_short | Regorafenib induces NOX5-mediated endoplasmic reticulum stress and potentiates the anti-tumor activity of cisplatin in non-small cell lung cancer cells |
| title_sort | regorafenib induces nox5 mediated endoplasmic reticulum stress and potentiates the anti tumor activity of cisplatin in non small cell lung cancer cells |
| topic | NSCLC Regorafenib Cisplatin Reactive oxygen species NOX5 |
| url | http://www.sciencedirect.com/science/article/pii/S1476558623000222 |
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