Doxorubicin-Induced Systemic Inflammation Is Driven by Upregulation of Toll-Like Receptor TLR4 and Endotoxin Leakage.
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.
State Key Laboratory of Pharmaceutical Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of life sciences, Nanjing University, Nanjing, China.
Lintao
L
Wang
State Key Laboratory of Pharmaceutical Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of life sciences, Nanjing University, Nanjing, China.
Qian
Q
Chen
State Key Laboratory of Pharmaceutical Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of life sciences, Nanjing University, Nanjing, China.
Haixia
H
Qi
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau SAR.
Chunming
C
Wang
State Key Laboratory of Pharmaceutical Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of life sciences, Nanjing University, Nanjing, China.|Department of Clinical Laboratory, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
Cheng
C
Wang
State Key Laboratory of Pharmaceutical Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of life sciences, Nanjing University, Nanjing, China. leidong@nju.edu.cn jfzhang@nju.edu.cn.
Junfeng
J
Zhang
State Key Laboratory of Pharmaceutical Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of life sciences, Nanjing University, Nanjing, China. leidong@nju.edu.cn jfzhang@nju.edu.cn.
Lei
L
Dong
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D004317:Doxorubicin / Q000009:adverse effects*; D004731:Endotoxins; D006801:Humans; D007249:Inflammation / Q000139:chemically induced*; D051379:Mice; D008810:Mice, Inbred C57BL; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D015854:Up-Regulation
D000903:Antibiotics, Antineoplastic; D004731:Endotoxins; D051197:Toll-Like Receptor 4; D004317:Doxorubicin