Regorafenib induces NOX5-mediated endoplasmic reticulum stress and potentiates the anti-tumor activity of cisplatin in non-small cell lung cancer cells

  • Neoplasia. 2023 Mar 18;39:100897. doi: 10.1016/j.neo.2023.100897.
Hehuan Sui  1 ,  Sisi Xiao  2 ,  Suping Jiang  1 ,  Siyuan Wu  1 ,  Haizhen Lin  3 ,  Liyuan Cheng  1 ,  Lihua Ye  1 ,  Qi Zhao  1 ,  Yun Yu  4 ,  Lu Tao  4 ,  Feng-Ming Kong  5 ,  Xiaoying Huang  6 ,  Ri Cui  7
Affiliations
  • 1. 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.
  • 2. 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; The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
  • 3. Cancer 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, China.
  • 4. Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 5. The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China. Electronic address: [email protected].
  • 6. The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China. Electronic address: [email protected].
  • 7. 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. Electronic address: [email protected].
PMID: 36940556 DOI: 10.1016/j.neo.2023.100897
Abstract

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.

Keywords
Cisplatin; NOX5; NSCLC; Reactive oxygen species; Regorafenib.
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