Quercetin supplementation attenuates the progression of cancer cachexia in ApcMin/+ mice

Abstract

Although there are currently no approved treatments for cancer cachexia, there is an intensified interest in developing therapies because of the high mortality index associated with muscle wasting diseases. Successful treatment of the cachectic patient focuses on improving or maintaining body weight and musculoskeletal function. Nutraceutical compounds, including the natural phytochemical quercetin, are being examined as potential treatments because of their anti-inflammatory, antioxidant, and anticarcinogenic properties. The purpose of this study was to determine the effect of quercetin supplementation on the progression of cachexia in the adenomatous polyposis coli (Apc)(Min/+) mouse model of colorectal cancer. At 15 wk of age, C57BL/6 and male Apc(Min/+) mice were supplemented with 25 mg/kg of quercetin or vehicle solution mix of Tang juice and water (V) daily for 3 wk. Body weight, strength, neuromuscular performance, and fatigue were assessed before and after quercetin or V interventions. Indicators of metabolic dysfunction and inflammatory signaling were also assessed. During the treatment period, the relative decrease in body weight in the Apc(Min/+) mice gavaged with V (Apc(Min/+)V; -14% ± 2.3) was higher than in control mice gavaged with V (+0.6% ± 1.0), control mice gavaged with quercetin (-2% ± 1.0), and Apc(Min/+) mice gavaged with quercetin (Apc(Min/+)Q; -9% ± 1.3). At 18 wk of age, the loss of grip strength and muscle mass shown in Apc(Min/+)V mice was significantly attenuated (P < 0.05) in Apc(Min/+)Q mice. Furthermore, Apc(Min/+)V mice had an induction of plasma interleukin-6 and muscle signal transducer and activator of transcription 3 phosphorylation, which were significantly (P < 0.05) mitigated in Apc(Min/+)Q mice, despite having a similar tumor burden. Quercetin treatment did not improve treadmill run-time-to-fatigue, hyperglycemia, or hyperlipidemia in cachectic Apc(Min/+) mice. Overall, quercetin supplementation positively affected several aspects of cachexia progression in mice and warrants further exploration as a potential anticachectic therapeutic.

FIGURE 1

Quercetin bioavailability in plasma in C57BL/6 mice and percentage change in body weight, fat, and muscle mass in C57BL/6 and Apc^Min/+ mice supplemented with vehicle or quercetin via oral gavage. Plasma quercetin concentrations (n = 3/time point) (A). Percentage change in body weight pre- and post-intervention (B), epididymal fat (C), and muscle mass (D) at 18 wk of age. Values are means ± SEMs, n = 4–8/group. Means without a common letter differ, P < 0.05. Apc, adenomatous polyposis coli; Apc^Min/+Q, Apc^Min/+ mice gavaged with quercetin; Apc^Min/+V, Apc^Min/+ mice gavaged with vehicle solution mix of Tang juice and water; C57BL/6-Q, control mice gavaged with quercetin; C57BL/6-V, control mice gavaged with vehicle solution mix of Tang juice and water; Gastroc, gastrocnemeous; Gen, genotype; Int, interaction; M.E., main effect; Quad, quadriceps; vehicle, vehicle solution mix of Tang juice and water.

FIGURE 2

Functional tests in Apc^Min/+ mice supplemented with vehicle or quercetin via oral gavage at 15 and 18 wk of age. Grip strength (A), rotorod (B), and run-time-to-fatigue tests (C). Values are means ± SEMs, n = 5/group. Dotted line represents the mean of C57BL/6 mice. *P < 0.05, significant difference from Apc^Min/+V and Apc^Min/+Q pre-intervention. ^P < 0.05, significant difference from Apc^Min/+V post-intervention. Apc, adenomatous polyposis coli; Apc^Min/+Q, Apc^Min/+ mice gavaged with quercetin; Apc^Min/+V, Apc^Min/+ mice gavaged with vehicle solution mix of Tang juice and water; M.E., main effect; Post, 18 wk of age; Pre, 15 wk of age; Treat, treatment; vehicle, vehicle solution mix of Tang juice and water.

FIGURE 3

Metabolic measurements in C57BL/6-V and Apc^Min/+ mice supplemented with vehicle or quercetin via oral gavage at 18 wk of age. Blood glucose (A), plasma insulin (B), HOMA index (C), and plasma TGs (D). Values are means ± SEMs, n = 4–7/group. Means without a common letter differ, P < 0.05. Apc, adenomatous polyposis coli; Apc^Min/+Q, Apc^Min/+ mice gavaged with quercetin; Apc^Min/+V, Apc^Min/+ mice gavaged with vehicle solution mix of Tang juice and water; C57BL/6-V, control mice gavaged with vehicle solution mix of Tang juice and water; vehicle, vehicle solution mix of Tang juice and water.

FIGURE 4

Systemic and local inflammatory signaling of C57BL/6 and Apc^Min/+ mice supplemented with vehicle or quercetin via oral gavage at 18 wk of age. Plasma concentration of IL-6, values are means ± SEMs, n = 4–8/group (A). Activation of NF-κB, values are means ± SEMs, n = 4/group (B). STAT3, values are means ± SEMs, n = 4/group (C) in the quadriceps muscle. Means without a common letter differ, P < 0.05. *P < 0.05, significant differences between Apc^Min/+V and Apc^Min/+Q. Apc, adenomatous polyposis coli; Apc^Min/+Q, Apc^Min/+ mice gavaged with quercetin; Apc^Min/+V, Apc^Min/+ mice gavaged with vehicle solution mix of Tang juice and water; C57BL/6-Q, control mice gavaged with quercetin; C57BL/6-V, control mice gavaged with vehicle solution of Tang juice and water; Gen, genotype; Int, interaction; M.E., main effect; pNF-κB, phosphorylated NF-κB; pSTAT3, phosphorylated signal transducer and activator of transcription 3; STAT3, signal transducer and activator of transcription 3; vehicle, vehicle solution mix of Tang juice and water.