2. Academic Validation
  3. Piperlongumine induces ROS accumulation to reverse resistance of 5-FU in human colorectal cancer via targeting TrxR

Piperlongumine induces ROS accumulation to reverse resistance of 5-FU in human colorectal cancer via targeting TrxR

  • Eur J Pharmacol. 2025 Mar 5:997:177478. doi: 10.1016/j.ejphar.2025.177478.
Ji Zhou 1,  Qing-Ju Shu 2,  Tian Wang 2,  Hui-Dan Huang 2,  Sheng-Peng Zhang 2,  Jing Zhang 3,  Yong-Qiu Zheng 4,  Chao Zhang 5
Affiliations

Affiliations

  • 1 Center for Reproductive Medicine, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, 241000, PR China.
  • 2 Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines in Southern Anhui, School of Pharmacy, Wannan Medical College, Wuhu, Anhui, 241000, PR China.
  • 3 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, PR China. Electronic address: jingjing-506@hotmail.com.
  • 4 Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines in Southern Anhui, School of Pharmacy, Wannan Medical College, Wuhu, Anhui, 241000, PR China. Electronic address: yongqiuzheng@sina.com.
  • 5 Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines in Southern Anhui, School of Pharmacy, Wannan Medical College, Wuhu, Anhui, 241000, PR China. Electronic address: zhangchao@wnmc.edu.cn.
PMID: 40054719 DOI: 10.1016/j.ejphar.2025.177478
Abstract

Resistance is a major concern for colorectal Cancer patients undergoing chemotherapy. Piperlongumine (PL) has been proven to effectively reverse drug resistance in several types of cancers; however, the mechanisms associated with the reversal effect and the targets of PL in Cancer Drug Resistance are still unclear. In this research, the reversal effects and associated mechanisms of PL in 5-Fluorouracil (5-FU) resistance colorectal Cancer were investigated both in vitro and in vivo. Our data revealed that PL acted as a ROS inducer via binding and inhibiting TrxR (IC50 around 10.17 μM). By inducing ROS accumulation, PL reversed resistance to 5-FU in HCT-8/5-FU cells (reversal ratio: 4.9-fold) and enhanced the therapeutic effects of 5-FU through the dephosphorylation of Akt in BALB/c athymic nude mice bearing HCT-8/5-FU tumor xenografts. As a ROS inducer, PL reversed resistance to 5-FU by directly promoting inhibition of Akt phosphorylation, and further inhibited 5-FU efflux and promoted cell Apoptosis through affecting the Akt/Foxo3/NRF2/P-gp and Akt/Foxo3/NRF2/BAD signaling pathway.

Keywords

Colorectal cancer; Drug resistance; Piperlongumine; Thioredoxin reductase.

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