Gemcitabine and XCT790, an ERRα inverse agonist, display a synergistic anticancer effect in pancreatic cancer

• Published in: International journal of medical sciences 2022-01, Vol.19 (2), p.286-298
• Main Authors: Liu, Shi-Lei, Liang, Hai-Bin, Yang, Zi-Yi, Cai, Chen, Wu, Zi-You, Wu, Xiang-Song, Dong, Ping, Li, Mao-Lan, Zheng, Lei, Gong, Wei
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis; Apoptosis - drug effects; Cancer therapies; Cell cycle; Cell Cycle - drug effects; Chemotherapy; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Drug dosages; Drug Synergism; Epithelial-Mesenchymal Transition - drug effects; ERRalpha Estrogen-Related Receptor; Gemcitabine; Humans; Laboratory animals; MAP Kinase Signaling System - drug effects; Nitriles - pharmacology; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Reagents; Receptors, Estrogen - drug effects; Research Paper; Thiazoles - pharmacology; Xenograft Model Antitumor Assays
• ISSN: 1449-1907; 1449-1907
• DOI: 10.7150/ijms.68404

Pancreatic cancer (PC) is one of the most fatal and chemoresistant malignancies with a poor prognosis. The current therapeutic options for PC have not achieved satisfactory results due to drug resistance. Therefore, it is urgent to develop novel treatment strategies with enhanced efficacy. This study sought to investigate the anticancer effect of gemcitabine and XCT790, an estrogen-related receptor alpha (ERRα) inverse agonist, as monotherapies or in combination for the treatment of PC. Here we demonstrated that the drug combination synergistically suppressed PC cell viability, its proliferative, migratory, invasive, apoptotic activities, and epithelial-to-mesenchymal transition (EMT), and it triggered G0/G1 cell cycle arrest and programmed cell death in vitro. In addition, in vivo assays using xenograft and mini-PDX (patient-derived xenograft) models further confirmed the synergistic antitumor effect between gemcitabine and XCT790 on PC. Mechanistically, gemcitabine and XCT790 suppressed PC by inhibiting ERRα and MEK/ERK signaling pathway. In conclusion, our current study demonstrated for the first time that gemcitabine combined with XCT790 displayed synergistic anticancer activities against PC, suggesting that their combination might be a promising treatment strategy for the therapy of PC.