Induction of IL-6 by Cytotoxic Chemotherapy Is Associated With Loss of Lean Body and Fat Mass in Tumor-free Female Mice - PubMed (original) (raw)

Induction of IL-6 by Cytotoxic Chemotherapy Is Associated With Loss of Lean Body and Fat Mass in Tumor-free Female Mice

Collin R Elsea et al. Biol Res Nurs. 2015 Oct.

Abstract

Cancer patients treated with cytotoxic chemotherapy experience fatigue and changes in body composition that can impact physical functioning and quality of life during and after treatment. Interleukin-6 (IL-6) is associated with fatigue in cancer survivors and plays an important role in the regulation of body composition. The purpose of the present study was to determine the specific role of IL-6 in cyclophosphamide-doxorubicin-5-fluorouracil (CAF)-induced changes in fatigue, food intake, and body composition using mice lacking IL-6. Female wild-type (WT) and IL-6 (-/-) mice were injected with four cycles of CAF or normal saline (NS) administered at 21-day intervals. Daily voluntary wheel-running activity (VWRA), used as a proxy for fatigue, and food intake were monitored daily up to 21 days after the fourth dose. Dual-energy X-ray absorptiometry (DEXA) was used to assess treatment-related changes in lean body mass (LBM), fat mass (FM), and bone mineral content (BMC). Patterns of change in fatigue and food intake did not differ between CAF-treated WT and IL-6 (-/-) mice. However, a Genotype × Drug interaction was observed for LBM (p = 0.047) and FM (p = 0.035) but not BMC (p = .569). Whereas WT mice lost LBM and FM during CAF treatment, IL-6-deficient mice did not. Treatment-related decreases in levels of the anabolic hormone insulin-like growth factor-1 (IGF-1) may contribute to LBM and FM loss since CAF decreased IGF-1 levels in an IL-6-dependent manner. These findings implicate IL-6 and possibly IGF-1 in the regulation of body composition in breast cancer patients exposed to cytotoxic chemotherapy.

Keywords: IL-6; body composition; cachexia; doxorubicin; fatigue.

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Conflict of interest statement

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1

Cytotoxic cancer chemotherapy increases circulating inter-leukin (IL)-6 levels in wild-type (WT) mice relative to normal saline (NS)-treated mice. Fold increase in serum levels of IL-6 in cyclopho-sphamide-doxorubicin-5-fluorouracil (CAF)-treated (n = 50) relative to normal NS-treated mice (n = 50) sacrificed at 1, 3, 6, 14, and 24 hr postinjection (n = 4–5 mice per group per time point). Each bar represents the mean ± standard error of mean (SEM) of each value. The asterisks indicate a statistically significant difference in serum protein level (pg/mL) between groups. ***p < .0001.

Figure 2

Cytotoxic chemotherapy–induced changes in voluntary wheel-running activity (VWRA) in wild-type (WT) and IL-6_−/− mice. A, Daily VWRA and food intake in (i) WT and (ii) IL-6_−/− mice injected with cyclophosphamide-doxorubicin-5-fluorouracil (CAF; n = 17, filled circle) or normal saline (NS; n = 20 open circle). The black arrows represent the time points at which mice were administered CAF or NS. One-way analysis of variance (ANOVA) was used to detect differences between the CAF and NS groups. Each data point represents the mean of each value. Error bars are not included to allow discrimination of data trends. (B) Dark-phase change from baseline in average (i) time on wheel, (ii) distance run, (iii) and speed, and in (iv) peak speed calculated at Time 1 (the three dark phases following the first CAF injection) and Time 2 (the last three dark phases of the study prior to body composition analysis). Two-way ANOVA was used to detect significant Treatment × Genotype interactions (see underlined p values above each bar cluster). Each bar represents the mean ± standard error of mean (SEM) of each value. *p < .05, **p < .001, ***p < .0001, †_p = .065, and ††_p = .116 for comparison between treatment groups within genotypes.

Figure 3

Cytotoxic chemotherapy–induced changes in food intake in wild-type (WT) and _IL-6_−/− mice. Daily food intake in (i) WT and (ii) _IL-6_−/− mice injected with cyclophosphamide-doxorubicin-5-fluorouracil (CAF; n = 17, filled circle) or normal saline (NS; n = 20, open circle). The black arrows represent the time points at which mice were administered CAF or NS. One-way analysis of variance (ANOVA) was used to detect differences between the CAF and NS groups. Each data point represents the mean of each value. Error bars are not included to allow discrimination of data trends. *p < .05 for comparison between treatment groups within genotypes.

Figure 4

Cytotoxic chemotherapy–induced changes in body composition in wild-type (WT) and _IL-6_−/− mice. Body composition analysis was performed 3 weeks before and 3 weeks after treatment. Bars show mean treatment-related changes in fat mass (FM), lean body mass (LBM), and bone mineral content (BMC) derived from pre- and posttreatment dual-energy absorptiometry (DEXA) scans on cyclo-phosphamide-doxorubicin-5-fluorouracil (CAF)- or normal saline (NS)-treated wild-type (WT) and IL-6-deficient mice. Two-way analysis of variance (ANOVA) was used to detect significant Treatment × Genotype interactions (see underlined p values above each bar cluster). *p < .05, **p < .001, and ***p < .0001 for comparison between treatment groups within genotypes.

Figure 5

Effects of cytotoxic chemotherapy treatment on circulating insulin-like growth factor (IGF)-1 levels in wild-type (WT) and _IL-6_−/− mice. A, Serum levels of IGF-1 in nonfasted WT mice 24 hr after injection with cyclophosphamide-doxorubicin-5-fluorouracil (CAF) or normal saline (NS). Each bar represents the mean ± standard error of mean (SEM) of each value. B, Fold increase in fasting serum IGF-1 levels in CAF-treated WT and IL-6-deficient mice relative to NS-treated controls at 14 hr postinjection. Each bar represents the mean ± SEM of each value. *p < .05 for comparison of IGF-1 level (A) or change (B) between groups.

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Induction of IL-6 by Cytotoxic Chemotherapy Is Associated With Loss of Lean Body and Fat Mass in Tumor-free Female Mice - PubMed (original) (raw)