journal contribution
posted on 2023-03-31, 00:27 authored by Lintao Wang, Qian Chen, Haixia Qi, Chunming Wang, Cheng Wang, Junfeng Zhang, Lei Dong Supplemental informantion included partial data which verified that ET is a direact cause of the side efforts of DOX and data which verified that mTOR signaling pathway play a role in DOX-induced systemic inflammation.
Funding
National Basic Research Program of China
National High Technology Research and Development
New Century Excellent Talents in University
National Natural Science Foundation of China
Macau Science and Technology Fund
University of Macau
History
ARTICLE ABSTRACT
Doxorubicin is one of the most effective chemotherapeutic agents used for cancer treatment, but it causes systemic inflammation and serious multiorgan side effects in many patients. In this study, we report that upregulation of the proinflammatory Toll-like receptor TLR4 in macrophages by doxorubicin is an important step in generating its toxic side effects. In patient serum, doxorubicin treatment resulted in leakage of endotoxin and inflammatory cytokines into circulation. In mice, doxorubicin damaged the intestinal epithelium, which also resulted in leakage of endotoxin from the gut flora into circulation. Concurrently, doxorubicin increased TLR4 expression in macrophages both in vitro and in vivo, which further enhanced the sensitivity of these cells to endotoxin. Either depletion of gut microorganisms or blockage of TLR4 signaling effectively decreased doxorubicin-induced toxicity. Taken together, our findings suggest that doxorubicin-triggered leakage of endotoxin into the circulation, in tandem with enhanced TLR4 signaling, is a candidate mechanism underlying doxorubicin-induced systemic inflammation. Our study provides new insights for devising relevant strategies to minimize the adverse effects of chemotherapeutic agents such as doxorubicin, which may extend its clinical uses to eradicate cancer cells. Cancer Res; 76(22); 6631–42. ©2016 AACR.
