Doxorubicin-Induced Systemic Inflammation Is Driven by Upregulation of Toll-Like Receptor TLR4 and Endotoxin Leakage

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 doxorubicininduced 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. Ó2016 AACR.

Physiological levels of chromogranin A prevent doxorubicin‐induced cardiotoxicity without impairing its anticancer activity

“…can protect rats from Doxo-induced inflammation, cardiac fibrosis and damage, and from I/R heart injury. It is well known that Doxo can cause toxicity and inflammation in several organs, including the heart, liver and intestine (39,54). In particular, Doxo can cause the release of proinflammatory cytokines in the blood of patients, such as IL-1b and TNF-a (39), and the release of ROS, cTnT, and LDH, markers of cytotoxic and cardiotoxic responses (1,(40)(41)(42).…”

“…It is well known that Doxo can cause toxicity and inflammation in several organs, including the heart, liver and intestine (39,54). In particular, Doxo can cause the release of proinflammatory cytokines in the blood of patients, such as IL-1b and TNF-a (39), and the release of ROS, cTnT, and LDH, markers of cytotoxic and cardiotoxic responses (1,(40)(41)(42). In the heart, inflammation is stimulated by Doxo-induced cell apoptosis and tissue damage; this effect involves the activation of the TNF signaling pathway, the generation of massive ROS, and the persistent expression of multiple proinflammatory cytokines such as IL-1b and TNF-a (39,55,56).…”

“…Thus, the heart itself can be an important source of inflammatory and damage markers. In addition, Doxo, by disrupting the gut epithelium, can induce a significant release of endotoxins into the circulation, thereby contributing to systemic inflammation and multiorgan damage (39).…”

Parabacteroides distasonis attenuates toll‐like receptor 4 signaling and Akt activation and blocks colon tumor formation in high‐fat diet‐fed azoxymethane‐treated mice

“…The recognition of bacterial LPS by toll‐like receptor 4 (TLR4) is known to trigger a cascade of cellular signaling to induce inflammation. In fact, it is demonstrated that overexpression of TLR4 promotes systemic inflammation and intestinal neoplasia in mice . Compelling evidence indicates that elevated inflammation constitutes a major mechanistic link between obesity and increased tumor risk .…”

Crosstalk between E2F1 and P53 transcription factors in doxorubicin-induced DNA damage: evidence for preventive/protective effects of silymarin

“…Despite the fact that DOX is one of the first line agents in cancer therapy, its serious side effects including haematological, cardio‐ and nephrotoxicity limit its conventional uses . There is a recent report indicating a DOX‐induced systemic inflammation due to leakage of endotoxin into the circulation and consequently enhancement of TLR‐4 signalling . In paediatric practice, DOX is used to treat the testicular tumours, which may also cause testicular dysfunction, characterized by cellular apoptosis‐related damages …”