Tubeimoside-I, an inhibitor of HSPD1, enhances cytotoxicity of oxaliplatin by activating ER stress and MAPK signaling pathways in colorectal cancer

  • J Ethnopharmacol. 2025 Jan 10:336:118754. doi: 10.1016/j.jep.2024.118754.
Tao Wu  1 ,  Yun Yu  2 ,  Xinyue Tu  2 ,  Lihua Ye  2 ,  Jiaying Wang  2 ,  Chenjun Xie  2 ,  Keke Kuang  2 ,  Ying Yu  2 ,  Weishan Zhuge  2 ,  Zhonglin Wang  3 ,  Ri Cui  4 ,  Yihu Zheng  5
Affiliations
  • 1. Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China; Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
  • 2. Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
  • 3. The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325003, China.
  • 4. Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. Electronic address: [email protected].
  • 5. Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China; Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. Electronic address: [email protected].
PMID: 39208999 DOI: 10.1016/j.jep.2024.118754
Abstract

Ethnopharmacological relevance: Tubeimoside-I (TBM) promotes various Cancer cell death by increasing the Reactive Oxygen Species (ROS) production. However, the specific molecular mechanisms of TBM and its impact on oxaliplatin-mediated anti-CRC activity are not yet fully understood.

Aim of the study: To elucidate the therapeutic effect and underlying molecular mechanism of TBM on oxaliplatin-mediated anti-CRC activity.

Materials and methods: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, wound healing assays and flow cytometry were conducted to investigate the changes in cell phenotypes and ROS generation. Real-time quantitative PCR (qRT-PCR) and western blotting were performed to detect the expressions of related mRNA and proteins. Finally, mouse xenograft models demonstrated that synergistic anti-tumor effects of combined treatment with TBM and oxaliplatin.

Results: The synergistic enhancement of the anti-tumor effects of oxaliplatin in colon Cancer cells by TBM involved in the regulation of ROS-mediated endoplasmic reticulum (ER) stress, C-jun-amino-terminal kinase (JNK), and p38 MAPK signaling pathways. Mechanistically, TBM increased ROS generation in colon Cancer cells by inhibiting heat shock protein 60 (HSPD1) expression. Knocking down HSPD1 increased TBM-induced antitumor activity and ROS generation in colon Cancer cells. The mouse xenograft tumor models further validated that the combination therapy exhibited stronger anti-tumor effects than monotherapy alone.

Conclusions: Combined therapy with TBM and oxaliplatin might be an effective therapeutic strategy for some CRC patients.

Keywords
Colorectal cancer; ER stress; HSPD1; Oxaliplatin; ROS; Tubeimoside-I.
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