Dietary Quercetin Reduces Chemotherapy-Induced Fatigue in Mice

Abstract

Purpose. While fatigue is the most commonly reported symptom of chemotherapy, there are currently no effective treatments for chemotherapy-induced fatigue (CIF). We used a mouse model to examine the benefits of quercetin on CIF as measured by voluntary wheel running activity and sought to determine whether quercetin may be associated with a decrease in inflammation and/or anemia. Methods. Mice were assigned to 1 of 4 groups: placebo-vehicle (Plac-PBS), placebo-5-fluorouracil (Plac-5FU), quercetin-vehicle (Quer-PBS), or quercetin-5-fluorouracil (Quer-5FU). All mice were given a daily injection of either 60 mg/kg of 5-FU or phosphate buffered saline (PBS) for 5 days. Quercetin (0.02%) treatment was administered in the food 3 days prior to 5-FU administration and for the duration of the experiment (ie, days −2 to 14). A second group of mice was sacrificed at 5 and 14 days post initial injection for assessment of monocyte chemoattractant protein-1 (MCP-1) and anemia. Results. Voluntary wheel running was reduced in both the Plac-5FU and Quer-5FU groups following 5-FU injection (P < .05). However, the Quer-5FU group recovered to baseline levels by approximately day 7, whereas the Plac-5FU group remained suppressed. MCP-1 was significantly elevated at 14 days in Plac-5FU (P < .001), but no changes were seen with Quer-5FU. Treatment with 5-FU resulted in anemia at both 5 days and 14 days; however, quercetin blocked this effect at 14 days (P < .001). Conclusion. These results demonstrate the beneficial effect of quercetin on improving recovery of voluntary physical activity following 5-FU treatment, which may be linked to a decrease in inflammation and anemia.

Introduction

More than 13 million Americans are currently diagnosed with cancer. ¹ A large majority of these patients undergo chemotherapy treatment, the side effects of which can be devastating. Chemotherapy symptoms can range from pain and nausea to impaired concentration and depression, some so severe that they have been identified as a major health problem themselves. ² The most commonly reported symptom of chemotherapy treatment is fatigue, which is reported in as many as 80% to 99% of patients who are currently undergoing treatment. ³ This type of fatigue may drastically affect quality of life (QOL),^4,5 self-care capabilities,^3,6 desire to continue treatment, ⁶ and consequently overall survival. The underlying mechanisms for chemotherapy-induced fatigue (CIF) have not yet been completely elucidated but are likely to include inflammation and anemia, among others,^3,7,8

There is evidence to support a role of inflammation in the development of CIF. Tissue damage caused by chemotherapy is thought to induce the release of cytokines such as interleukin (IL)-1β,α, tumor necrosis factor (TNF)-α, interleukin-6, and interferon (IFN)-β,γ,^8,9 all of which have well-established links to fatigue. In fact, in patients undergoing concurrent chemoradiation therapy, fatigue was associated with increased IL-6 and TNF-αR1 ¹⁰ and with activation of the NF-κB pathway in patients recovering from breast cancer. ¹¹ Previous work in our laboratory has demonstrated that circulating monocyte chemoattractant protein 1 (MCP-1), which is often expressed concurrently with TNF-α and IL-1β, ¹² is associated with fatigue in a mouse model of CIF that we developed. ¹³ Others have recently confirmed this relationship; Weymann et al ¹⁴ demonstrated that MCP-1 was elevated in conjunction with other inflammatory cytokines following a cytotoxic chemotherapy cocktail that included 5-FU. Consistent with this, we have reported that MCP-1-deficient mice have a heightened recovery from CIF as measured by voluntary wheel running activity. ¹³ There is also evidence that a diminished production of blood cells following chemotherapy treatment may contribute to CIF. In fact, a decrease in red blood cell production, leading to anemia, has been identified by the National Comprehensive Cancer Network as one of the treatable factors of CIF. Incidence of anemia ranges from 40% to 90% in chemotherapy patients, varying by stage and type of cancer as well as chemotherapy intensity. ⁸

Although there is evidence that CIF is mediated, at least in part, by inflammatory processes, nonsteroidal anti-inflammatory drugs (NSAIDs) are rarely used in the treatment of CIF; traditional NSAIDs are associated with serious side effects including gastrointestinal distress and ulcers. ¹⁵ Quercetin, a well-characterized flavonol, has been shown to have anti-inflammatory properties ¹⁵ and may provide a unique therapeutic strategy for CIF. For example, it has been reported to blunt the NF-κB signaling pathway as well as inflammatory cytokines such as TNF-α in a variety of models.^16,17 Quercetin also has direct effects on MCP-1; Panicker et al ¹⁸ demonstrated the efficacy of quercetin in reducing MCP-1 gene expression in aortic endothelial cells, and Chuang et al ¹⁹ reported that it can attenuate MCP-1 secretion from adipocytes. Quercetin may also blunt chemotherapy-induced anemia. In models of oxidative damage, quercetin has been shown to protect erythrocytes against hemolysis and premature apoptosis.^20,21 Given quercetin’s potent anti-inflammatory activity, its documented effects on anemia, and its widespread availability, ¹⁶ it may serve as an effective therapeutic strategy to reduce CIF.

The purpose of this investigation was to examine the potential benefits of quercetin in reducing CIF as measured by voluntary wheel running activity and, further, to determine whether these effects may be associated with a decrease in inflammation and/or anemia. Because both cancer and cancer treatments are known to cause fatigue, we examined the effects of quercetin on chemotherapy independent of cancer using wild-type, non–tumor-bearing mice; this allowed us to specifically establish the benefits of quercetin on CIF. This study design is consistent with previous work by Wood et al, ⁸ Ray et al, ²² and Weymann et al ¹⁴ that examined chemotherapy effects on fatigue in rodent models independent of cancer. Further, because we have shown that quercetin can reduce tumor burden in mice, ²³ any effects of quercetin on fatigue may have been attributable to a reduction in tumor burden and may not necessarily have been a direct effect on fatigue had this study been performed in tumor-bearing mice. We used 5-fluorouracil (5-FU) chemotherapy, the standard of care for colon cancer, in this study as it has been shown to induce fatigue in mice. ¹³ We used voluntary wheel running activity to measure fatigue; this is consistent with previous work in our laboratory ¹³ as well as others.^8,22 We hypothesized that quercetin would blunt the fatigue response following treatment with 5-FU and that this would be associated with a reduction in circulating MCP-1 and markers of anemia.

Methods

Mice

The study used C57BL/6 mice that were bred in the University of South Carolina’s Center for Colon Cancer Research (CCCR) Mouse Core Facility. At 6 weeks of age, mice either were housed individually in cages that contained a running wheel (Mini-Mitter, Bend, Oregon) (experiment 1) or were housed 4 to 5 per cage in a regular cage (experiment 2). To assess the effect of quercetin on voluntary wheel running activity (experiment 1), mice were randomly assigned to 1 of 4 groups; placebo-vehicle (Plac-PBS), placebo-5FU (Plac-5FU), quercetin-vehicle (Quer-PBS), or quercetin-5FU (Quer-5FU) (n = 11-12 per group). The effects of quercetin on MCP-1 and markers of anemia (experiment 2) were assessed by assigning mice to 1 of 6 groups; placebo-vehicle (Plac-PBS), placebo-5FU sacrificed at 5 days (Plac-5D), placebo-5FU sacrificed at 14 days (Plac-14D), quercetin-vehicle (Quer-PBS), quercetin-5FU sacrificed at 5 days (Quer-5D) and quercetin-5FU sacrificed at 14 days (Quer-14D) (n= 8/group). All mice were maintained on a 12:12 light-dark cycle in a low-stress environment and were given food and water ad libitum. All animal experimentation was approved by the University of South Carolina’s Institutional Animal Care and Use Committee.

Quercetin Feedings

Quercetin was incorporated into the rodent chow (AIN-76A Purified Diet) at a dose of 0.02%, which is equivalent to approximately 10 mg/d per mouse (Bio Serv, Frenchtown, New Jersey). This 0.02% dose of quercetin was selected based on recent data from our laboratory showing beneficial effects of quercetin feedings on tumor progression in the Apc^Min/+ mouse model of intestinal tumorigenesis. ²³ Typically, quercetin is either administered by gavage or incorporated into the rodent diet. Although gavage allows for more precise control of dosage, it also disturbs the animals’ wheel cage running activity, which was a primary outcome in our investigation. By incorporating quercetin into the diet, we aimed to avoid any behavioral perturbations, and the mode of delivery is more closely related to human quercetin consumption patterns. Mice received the 0.02% quercetin chow 3 days prior to 5-FU administration and remained on this diet for the duration of the experiment (ie, days −2 to 14). Timing of quercetin chow was based on pilot data from our laboratory (unpublished) in which we found physiological effects of quercetin after 3 days of supplementation. Others ²⁴ have confirmed that quercetin may take up to 3 days to accumulate in the tissues before physiological effects can be seen. To confirm that the mice did consume the quercetin diet, food consumption was measured daily. During the 3-day quercetin administration, mice consumed chow at an average of 4.61 ± 0.4 g/d per mouse, which is equivalent to 9.22 ± 0.8 mg of quercetin per mouse per day.

5-FU Treatment

The 5-FU (Sigma Chemical Co, St Louis, Missouri) was dissolved in phosphate buffered saline (PBS), pH 7.4, at 6.0 mg/10 mL. PBS alone was used as the vehicle injection. All treatments were sterile filtered and stored at 4°C for no more than 7 days. Mice were weighed immediately prior to injection and were given the 5-FU treatment or PBS in proportion to body weight (60 mg/kg) through intraperitoneal (i.p.) injection once per day for 5 days (days 1-5) at the onset of the dark cycle.

Experiment 1: Effects of Quercetin on Voluntary Wheel Running Activity in 5-FU-Treated Mice

Voluntary Activity

All mice (Plac-PBS, Plac-5FU, Quer-PBS, and Quer-5FU) were individually housed in cages with a running wheel (Mini Mitter, Bend, Oregon). Animals were allowed to acclimate to the wheels for a period of 7 days prior to any experimental treatment (previous data in our laboratory have shown that it takes approximately 7 days for mice to become acclimated to the running wheels). ²⁵ Following the acclimation period, voluntary activity (distance run, time on the wheel, and peak speed) was recorded for a period of 3 days to establish a baseline value. The quercetin diet was then introduced in Quer-PBS and Quer-5FU mice for 3 days prior to chemotherapy treatment and continued throughout the experiment (days Q1-Q3, Figure 1). After the baseline collection, injections began (days 1-5) and the mice were continually monitored (24 hours per day) through 14 days post initial injection (days 1-14). Voluntary activity was assessed for total distance (Distance), time on the wheel (Time), and peak speed (Speed) as calculated using the following equations: Distance = (no. of wheel rotations during a 2-minute interval) × [circumference of the running wheel (0.7581 m)]; Time = [(no. of 2-minute intervals where wheel rotations were >0) × 2]; Speed = (95th percentile of rotations during a given time interval) × [circumference of wheel (0.7581 m)/2]. Data are presented as the sum of all 2-minute intervals collected over the 12-hour active dark cycle and expressed as a percentage of baseline (average of data collected for 3 days before treatment).

Figure 1.

Change in voluntary activity following 5-fluorouracil (5-FU) treatment in placebo (Plac) and quercetin (Quer) mice (mean ± SEM). Quercetin treatment initiated on Q1-Q3, injections (phosphate buffered saline [PBS] and 5-FU) on days 1-5. ^@P < .05 between Quer-PBS and Quer-5FU, *P < .05 between Plac-PBS and Plac-5FU, ^#P < .05 between Quer-5FU and Plac-5FU. (A) Change from baseline in average distance run per night. (B) Change from baseline in average time run per night. (C) Change from baseline in average speed run per night.

Experiment 2: Effect of Quercetin on MCP-1 and Markers of Anemia in 5-FU-Treated Mice

Tissue Collection

Mice (Plac-PBS, Plac-5D, Plac-14D, Quer-PBS, Quer-5D, and Quer-14D) were sacrificed either 12 hours post final injection (day 5) or 10 days post final injection (day 14) via isoflurane overdose. Blood was collected from the inferior vena cava, and a sample of whole blood was analyzed using a VetScan (Abaxis, Union City, California). The remaining blood sample was centrifuged, and plasma was removed and stored at −80° until further analysis.

Anemia Markers

A complete blood count was performed using the VetScan HMT (Abaxis) for determination of red blood cells (RBCs), hematocrit (Hct) and hemoglobin (Hb). Briefly, 100 µL of whole blood was placed in an EDTA microtube and analyzed on the VetScan HMT according to the manufacturer’s instructions.

MCP-1 Concentration

Previous work in our laboratory has shown that plasma MCP-1 is associated with fatigue following 5-FU treatment. Further, we have reported that MCP-1^−/− mice have improved recovery from fatigue following a 5-day 5-FU treatment protocol. ¹³ Therefore, circulating MCP-1 was measured using a sandwich enzyme-linked immunosorbent assay (ELISA) (Quantikine, R&D Systems, Minneapolis, Minnesota) as previously described. ¹³

Statistics

Data were analyzed using commercial software (SigmaStat, SPSS, Chicago, Illinois). The voluntary activity data were analyzed by 3-way repeated-measures analysis of variance (ANOVA) to detect interaction (Time × Treatment × Diet). Post hoc analysis using a Bonferroni test was used to determine differences among groups on each day. Two-way ANOVA tests were used to detect a main effect of treatment and time for all blood/plasma measures. Statistical significance was set with an alpha value of P < .05. Data are presented as mean ± SEM.

Results

Experiment 1: Effects of Quercetin on Voluntary Wheel Running Activity in 5-FU-Treated Mice

Voluntary Activity

We examined the effects of quercetin on voluntary wheel running activity in mice treated with 5-FU chemotherapy. A main effect of treatment was found (P < .01) as well as a significant interaction between treatment and diet (P = .032). As previously reported, voluntary wheel running activity was significantly reduced as a result of 60 mg/kg 5-FU treatment (Figure 1). Specifically, 5-FU treatment decreased distance run beginning on day 1 (69.8% ± 9.7% for Plac-5FU versus 109.6% ± 18.4% for Plac-PBS) (P < .05) and this effect continued throughout the remainder of the analysis period (days 2-14) (P < .05). Similar effects were observed for time on the wheel; the Plac-5FU group ran significantly less time compared with Plac-PBS beginning on day 2 (74.49% ± 7.2% of baseline compared with 105.6% ± 8.9%) and continuing through day 14 (P < .05). On day 3 (89.1% ± 6.5% for Plac-5FU vs 110.6% ± 7.7% for Plac-PBS) through 14, peak speed was significantly different from the vehicle group (P < .05). However, mice receiving the quercetin treatment were only significantly different from their control (Quer-PBS) on days 2 to 7 for distance run, days 3 to 5 for time, and days 4 to 5 for speed (P < .05). Quer-5FU mice also recovered to baseline levels of activity by days 6 to 8, whereas the Plac-5FU group did not return to baseline levels for the duration of the experiment. The Quer-5FU group was also significantly higher than the Plac-5FU group on days 9 to 14 for distance and time and days 11 to 14 for speed (P < .05).

Experiment 2: Effect of Quercetin on MCP-1 and Markers of Anemia in 5-FU-Treated Mice

MCP-1 Concentration

MCP-1 concentration was measured in the plasma using an ELISA (Figure 2) at 5 days and 14 days post 5-FU treatment. There were no significant changes in MCP-1 concentration at 5 days for either the Plac-5D group (45.4 ± 2.2 ng/mL) or Quer-5D group (45.9 ± 4.0 ng/mL) compared with the non–5-FU-treated controls (Plac-PBS 38.3 ± 1.3 ng/mL and Quer-PBS 43.7 ± 3.4 ng/mL). However, at 14 days, the Plac-14D mice had a large increase in plasma MCP-1 (146.5 ± 22.08 ng/mL, P < .001), whereas the Quer-14D group (59.7 ± 7.04 ng/mL) was not significantly different from the non–5-FU-treated controls (Plac-PBS and Quer-PBS) at this time point.

Figure 2.

Change in plasma monocyte chemoattractant protein 1 (MCP-1) concentration in placebo (Plac) and quercetin (Quer) mice at 5 days and 14 days after treatment with 5-fluorouracil (mean ± SEM). *P < .001 between PLAC-14D and all groups.

Blood Analysis

At 5 days, RBCs were slightly lower in the Plac group (Plac-5D 8.03 ± 0.15 m/mm³) and significantly lower in the Quer group (Quer-5D 7.54 ± 0.22 m/mm³) compared with the Plac-PBS (8.35 ± 0.14 m/mm³) and Quer-PBS groups (8.42 ± 0.22 m/mm³) (P < .05) (Figure 3). However, the Plac-5D and Quer-5D were not different from each other. By 14 days, RBCs were significantly lower than baseline (Plac-PBS and Quer-PBS) for both the Plac-14D (4.18 ± 0.38 m/mm³) and Quer-14D groups (6.37 ± 0.20m/mm³) (Figure 3). However, this response was blunted with quercetin treatment; RBC count was significantly lower in the Plac-14D group compared with Quer-14D (P < .001). This same relationship was seen for both Hct and Hb; both Quer and Plac groups were lower at 5D, with Quer-5D significantly lower than Quer-PBS (P < .05), and both 14D groups were further reduced compared with vehicle (Plac-PBS and Quer-PBS, P < .05). Similar to RBCs, this response was blunted in the Quer group at 14 days.

Figure 3.

Effects of 5-fluorouracil on red blood cells (A), hematocrit (B), and hemoglobin (C) in placebo (Plac) and quercetin (Quer) mice 5 days and 14 days post treatment (mean ± SEM). *P < .05 difference from Plac-PBS and Quer-PBS, ^#P < .001 between Quer-14D and Plac-14D. PBS, phosphate buffered saline.

Discussion

Fatigue is the most commonly reported symptom of chemotherapy. In fact, it has been reported in as many as 80% to 99% of patients who are currently undergoing treatment. ³ To date, there are no effective treatments for CIF, ²⁶ which is not surprising given that the mechanisms responsible for this phenomenon have not yet been completely elucidated. It has been hypothesized that both inflammation and anemia, ⁷ which are well-characterized side effects of chemotherapy, may play a role in CIF. In fact, previous work from our research team has reported a 5-FU-induced increase in circulating MCP-1 and markers of anemia associated with fatigue in mice. ¹³ Naturally occurring bioactive dietary components that can target the side effects of chemotherapy may provide an effective therapeutic option for individuals undergoing chemotherapy. Therefore, the aim of this study was to determine the potential beneficial effects of the flavonol quercetin on fatigue in mice following chemotherapy treatment and, further, to explore the possible mechanisms for this effect. Our data indicate that quercetin can improve recovery of voluntary physical activity (distance, time on the wheel, and peak speed) following 5-FU administration. In addition, quercetin offset the increase in circulating MCP-1 and blunted the increase in anemia (Hb and Hct) that was evident at 14 days post 5-FU treatment. This study not only demonstrates quercetin’s efficacy in reducing fatigue following chemotherapy but also provides some insight into the potential mechanisms for its effects.

Although exact dosage and administration can vary depending on the specific cancer, typical chemotherapy treatment is given several days at a time over the course of weeks or months, and the fatigue experienced by cancer patients can last as long as or longer than the treatment duration (weeks to months after the completion of chemotherapy). Recently we developed a model of CIF in mice that was designed to mimic the treatment regime and resulting symptoms that have been reported in the clinical literature. ¹³ This model allows us to study the effects of CIF independent of cancer so that future treatment may be tailored specifically to address fatigue induced by chemotherapy. The current findings support our previously reported results of a detrimental effect of 5-FU on voluntary wheel running activity. Voluntary physical activity was significantly lower than the non–5-FU-treated control group beginning on the second day of treatment and remained depressed throughout the duration of the experiment (ie, up until day 14). While the quercetin group also had significantly lower levels of voluntary activity with 5-FU administration beginning on day 2 of treatment, they returned to baseline levels of activity, including distance run, time on the wheel, and peak speed, by day 8. We interpret this to mean that while quercetin was not able to block the initial effects of 5-FU on fatigue, it did have a significant impact on recovery of physical activity once the 5-FU treatment was ceased. These findings are supported, at least in part, by previous published studies from our laboratory; we recently reported a benefit of 7 days of quercetin on voluntary physical activity in healthy mice. ²⁵ However, in contrast to our previously reported findings, quercetin did not appear to increase physical activity in the non–5-FU-treated group (ie, healthy mice). The most likely explanation for these disparate findings is the treatment regime; in our previous study quercetin was administered via gavage and therefore in a single bolus, whereas in the current investigation quercetin was incorporated into the food resulting in smaller doses of quercetin consumed throughout the day. It is possible that a large dose is required to elicit the behavioral response seen in previous studies.

Given quercetin’s anti-inflammatory activity and our previous findings of a link between inflammation and CIF in mice, we next sought to determine the effects of quercetin on circulating MCP-1 following 5-FU administration. MCP-1 was measured in the plasma at baseline and at 5 days and 14 days post 5-FU. Previous work in this area has shown that increased levels of MCP-1 in the plasma are associated with fatigue following 5-FU chemotherapy ¹³ as well as other cytotoxic chemotherapies. ¹⁴ Likewise, MCP-1, in conjunction with other inflammatory cytokines, has been associated with increased fatigue in other chronic conditions including fibromyalgia ²⁷ and chronic fatigue syndrome. ²⁸ Here we report that quercetin supplementation completely blunted the MCP-1 response following chemotherapy treatment; MCP-1 was significantly elevated at 14 days following 5-FU, whereas when quercetin was given in combination with 5-FU there was no change in MCP-1 levels. These findings of a benefit of quercetin on inflammation are supported by previously reported studies. For example, quercetin has been previously shown to reduce or blunt the production of MCP-1 in an in vitro model of diabetic nephropathy ²⁹ as well as a high-fat diet–induced model of low-grade inflammation. ³⁰ Although not explored in the current investigation, quercetin most likely mediates these effects on inflammation by decreasing the activation of the NF-κB pathway and MCP-1 promoter gene expression.^16,18 Because MCP-1 was only measured at 5 and 14 days, we are unable to determine the time course of MCP-1 and fatigue, which is a limitation in this model. Further, our investigation was limited to measurement of MCP-1; given our previous findings of a role for MCP-1 in CIF and published reports of an effect of quercetin on MCP-1, we focused on this inflammatory mediator in the current investigation. However, it is important to point out that other inflammatory mediators have been shown to play a role on CIF and should be measured in future investigations to give a more comprehensive view of the inflammatory profile in this model.

Inflammatory cytokines are also associated with anemia, a common side effect of chemotherapy treatment. Elevated TNF-α and IL-1β, which can be initiated by MCP-1, may induce apoptosis of erythroid precursor cells and decrease erythropoietin production ³¹ as well as stimulate the production of hepcidin in liver cells, which diminishes the absorption of iron through the gut. ⁷ As quercetin has been shown to reduce inflammation, we next investigated its effects on markers of anemia. Following 5-FU treatment, both the placebo and quercetin groups showed decreased RBC, Hct, and Hb at 5 days; however, this effect was blunted in the quercetin group at day 14. While quercetin may have mediated this effect through a reduction in inflammation, it is also possible that this effect occurred via a reduction in 5-FU-induced oxidative damage. 5-FU causes anemia by damaging both the bone marrow and erythrocytes, inducing apoptosis, and reducing red blood cell production.^31,32 Prior studies have shown the potential role of quercetin in reducing anemia. For example, in a model of oxidative damage to erythrocytes by infection, quercetin was effective in preventing the drastic decrease in hemoglobin concentration in animals not only by preventing oxidative damage to erythrocytes but also by maintaining membrane integrity and preventing premature apoptosis. ²¹ Quercetin also has been reported to reduce oxidative hemolysis of red blood cells and enhance the resistance of the erythrocyte membrane to free radical damage. ⁹

It is important to note that the benefits of quercetin on CIF, MCP-1, and markers of anemia in this study occurred during the recovery period only; there were no beneficial effects of quercetin during the period of 5-FU administration. The most likely explanation for this is that a certain level of quercetin accumulation in the tissues is necessary to exert such positive effects. It is also possible that the quercetin treatment was not potent enough to overcome the effects of the 5-FU on CIF during the treatment period (days 1-5) but was beneficial during the recovery period (days 6-14) as the effects of the 5-FU diminished. Our interpretation of this observation is narrowed by the use of limited time points for analysis of MCP-1 and markers of anemia. Additionally, because this model only used non–tumor-bearing mice, it may not fully reflect CIF in those with cancer. However, it is important to understand the effects of chemotherapy alone so that effective treatment strategies can be developed to target the fatigue that is specifically associated with chemotherapy.

Overall, this study demonstrates the efficacy of dietary quercetin in reducing CIF in mice. Our data indicate that quercetin was effective at enhancing recovery of voluntary wheel running activity following 5-FU administration. To begin to determine the possible mechanisms for this effect, we examined factors that have been linked to CIF, including inflammation and anemia. In association with the benefits of quercetin on CIF, we report its beneficial effects on reducing plasma levels of MCP-1 and markers of anemia. Because the side effects of chemotherapy are so detrimental, quercetin may emerge as an important therapeutic treatment for reducing fatigue and improving quality of life in cancer patients.