2. Academic Validation
  3. Regorafenib activates oxidative stress by inhibiting SELENOS and potentiates oxaliplatin-induced cell death in colon cancer cells

Regorafenib activates oxidative stress by inhibiting SELENOS and potentiates oxaliplatin-induced cell death in colon cancer cells

  • Eur J Pharmacol. 2023 Aug 19;957:175986. doi: 10.1016/j.ejphar.2023.175986.
Yun Yu 1,  Tao Wu 1,  Xiaodong Zhang 2,  Pengfei Li 3,  Lihua Ye 3,  Jiayang Kuang 3,  Lu Tao 3,  Lianli Ni 3,  Qi Zhao 3,  Ji Zhang 3,  Huanle Pan 4,  Congying Xie 4,  Chenguo Zheng 5,  Shaotang Li 6,  Ri Cui 7
Affiliations

Affiliations

  • 1 Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China; Department of Radiotherapy Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
  • 2 Department of Colorectal Surgery, 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.
  • 4 Department of Radiotherapy Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China; Wenzhou Key Laboratory of Basic Science and Translational Research of Radiation Oncology, Wenzhou, Zhejiang, 325000, China.
  • 5 The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China. Electronic address: zhengchenguo80@163.com.
  • 6 Department of Colorectal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China. Electronic address: lishaotang163@163.com.
  • 7 Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China; Department of Radiotherapy Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China. Electronic address: wzmucuiri@163.com.
PMID: 37598924 DOI: 10.1016/j.ejphar.2023.175986
Abstract

Colorectal Cancer (CRC) is the third most common Cancer, and is one of the leading causes of cancer-related death worldwide. At the time of diagnosis, about 20% of patients with CRC present metastatic disease. Regorafenib, an oral multi-kinase inhibitor, has been demonstrated the efficacy and tolerability in patients with metastatic CRC. Oxaliplatin is a frontline treatment regimen for CRC, and combination treatments with oxaliplatin and Other chemotherapeutic agents exert superior therapeutic effects. However, side effects and drug resistance limited their further clinical application. Here, we found that combined treatment with regorafenib and oxaliplatin synergistically enhanced anti-tumor activities in CRC by activating Reactive Oxygen Species (ROS) mediated endoplasmic reticulum (ER) stress, C-Jun-amino-terminal kinase (JNK) and p38 signaling pathways. Regorafenib promoted ROS production by suppressing the expression of selenoprotein S (SELENOS). Knocking down SELENOS sensitized ROS-mediated anti-tumor effects of regorafenib in CRC cells. Furthermore, mouse xenograft models demonstrated that synergistic anti-tumor effects of combined treatment with regorafenib and oxaliplatin. This study provided solid experimental evidences for the combined treatment with regorafenib and oxaliplatin in CRC.

Keywords

Colorectal cancer; Oxaliplatin; Reactive oxygen species; Regorafenib; SELENOS.

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