6:2 Cl-PFESA, a proposed safe alternative for PFOS, diminishes the gemcitabine effectiveness in the treatment of pancreatic cancer

吉西他滨 胰腺癌 核苷酸还原酶 下调和上调 癌症研究 肿瘤科 医学 化疗 内科学 癌症 药理学 生物 遗传学 蛋白质亚单位 基因
作者
Jiawei Hong,Keyi Du,Weichen Zhang,Junran Chen,Hangbiao Jin,Yuanchen Chen,Yifan Jiang,Hanxi Yu,Xiaoyu Weng,Shusen Zheng,Jun Yu,Linping Cao
出处
期刊:Journal of Hazardous Materials [Elsevier]
卷期号:474: 134790-134790
标识
DOI:10.1016/j.jhazmat.2024.134790
摘要

Pancreatic ductal adenocarcinoma (PDAC)/pancreatic cancer, is a highly aggressive malignancy with poor prognosis. Gemcitabine-based chemotherapy remains the cornerstone of PDAC treatment. Nonetheless, the development of resistance to gemcitabine among patients is a major factor contributing to unfavorable prognostic outcomes. The resistance exhibited by tumors is modulated by a constellation of factors such as genetic mutations, tumor microenvironment transforms, environmental contaminants exposure. Currently, comprehension of the relationship between environmental pollutants and tumor drug resistance remains inadequate. Our study found that PFOS/6:2 Cl-PFESA exposure increases resistance to gemcitabine in PDAC. Subsequent in vivo trials confirmed that exposure to PFOS/6:2 Cl-PFESA reduces gemcitabine's efficacy in suppressing PDAC, with the inhibition rate decreasing from 79.5% to 56.7%/38.7%, respectively. Integrative multi-omics sequencing and molecular biology analyses have identified the upregulation of ribonucleotide reductase catalytic subunit M1 (RRM1) as a critical factor in gemcitabine resistance. Subsequent research has demonstrated that exposure to PFOS and 6:2 Cl-PFESA results in the upregulation of the RRM1 pathway, consequently enhancing chemotherapy resistance. Remarkably, the influence exerted by 6:2 Cl-PFESA exceeds that of PFOS. Despite 6:2 Cl-PFESA being regarded as a safer substitute for PFOS, its pronounced effect on chemotherapeutic resistance in PDAC necessitates a thorough evaluation of its potential risks related to gastrointestinal toxicity.
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