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.