The cancer chemotherapy drug etoposide (VP-16) induces proinflammatory cytokine production and sickness behavior-like symptoms in a mouse model of cancer chemotherapy-related symptoms.
Cancer chemotherapy-related symptoms such as fatigue, malaise, loss of interest in social activities, difficulty concentrating, and changes in sleep patterns can lead to treatment delays, dose reductions, or termination and have a profound effect on the physical, psychosocial, and economic aspects of quality of life. Clinicians have long suspected that these symptoms are similar to those associated with "sickness behavior," which is triggered by the production of the inflammatory cytokines IL-1beta, TNF-alpha, and IL-6 by macrophages and other cells of the innate immune system in response to immune challenge. The p38 mitogen-activated protein kinase (p38 MAPK) plays a central role in the production of these cytokines and consequently the induction of sickness behavior. Several cancer chemotherapy drugs have been shown to activate p38 MAPK, but whether these drugs can also induce the production of inflammatory cytokines to cause sickness behavior is unknown. The aim of this study was to determine whether the cancer chemotherapy drug etoposide (VP-16), which is known to activate p38 MAPK, could induce inflammatory cytokine production by murine macrophages and sickness-like behaviors when injected into mice. VP-16 activated p38 MAPK and induced IL-6 production in murine macrophages in a p38 MAPK- dependent manner. VP-16 administration rapidly increased serum levels of IL-6 in healthy mice and induced sickness-like behaviors as evidenced by a decrease in food intake, body weight, hemoglobin level, and voluntary wheel-running activity. These findings support the idea that the induction of IL-1beta, TNF-alpha, and IL-6 by cancer chemotherapy drugs underlies the fatigue and associated symptoms experienced by people undergoing cancer chemotherapy.
Wood
Lisa J
LJ
Oregon Health & Science University School of Nursing, 3455 SW US Veterans Hospital Road, Portland, OR 97239, USA. woodl@ohsu.edu
Nail
Lillian M
LM
Perrin
Nancy A
NA
Elsea
Collin R
CR
Fischer
April
A
Druker
Brian J
BJ
D000704:Analysis of Variance; D000818:Animals; D000855:Anorexia / Q000139:chemically induced; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D002100:Cachexia / Q000139:chemically induced; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D016903:Drug Monitoring; D005047:Etoposide / Q000009:adverse effects*; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D016899:Interferon-beta / Q000187:drug effects* / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D011788:Quality of Life; D012803:Sick Role; D012893:Sleep Wake Disorders / Q000139:chemically induced; D018709:Statistics, Nonparametric; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects* / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000502:physiology
D000972:Antineoplastic Agents, Phytogenic; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D005047:Etoposide; D016899:Interferon-beta; D048051:p38 Mitogen-Activated Protein Kinases