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

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

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: Kong0001@hku.hk.
  • 6 The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China. Electronic address: zjwzhxy@126.com.
  • 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: wzmucuiri@163.com.
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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