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Doxorubicin-induced systemic inflammation is driven by upregulation of toll-like receptor TLR4 and endotoxin leakage
Wang L.1; Chen Q.1; Qi H.1; Wang C.3; Wang C.1; Zhang J.1; Dong L.1
2016-11-15
Source PublicationCancer Research
ISSN15387445 00085472
Volume76Issue:22Pages:6631-6642
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.

DOI10.1158/0008-5472.CAN-15-3034
URLView the original
WOS Research AreaOncology
WOS SubjectOncology
WOS IDWOS:000388742100021
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Cited Times [WOS]:12   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Affiliation1.Nanjing University
2.Nanjing University, School of Medicine
3.University of Macau
Recommended Citation
GB/T 7714
Wang L.,Chen Q.,Qi H.,et al. Doxorubicin-induced systemic inflammation is driven by upregulation of toll-like receptor TLR4 and endotoxin leakage[J]. Cancer Research,2016,76(22):6631-6642.
APA Wang L..,Chen Q..,Qi H..,Wang C..,Wang C..,...&Dong L..(2016).Doxorubicin-induced systemic inflammation is driven by upregulation of toll-like receptor TLR4 and endotoxin leakage.Cancer Research,76(22),6631-6642.
MLA Wang L.,et al."Doxorubicin-induced systemic inflammation is driven by upregulation of toll-like receptor TLR4 and endotoxin leakage".Cancer Research 76.22(2016):6631-6642.
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