Research reportVoluntary wheel running ameliorates select paclitaxel chemotherapy-induced sickness behaviors and associated melanocortin signaling
Introduction
Chemotherapy drugs are instrumental components of cancer treatment that kill neoplastic tumor cells. Nevertheless, these drugs also kill dividing healthy cells and thereby contribute to a wide range of well-documented chemotherapy-related toxicities, including severe weight loss [1,2], anorexia [1,2], and fatigue [3,4]. Cancer-related fatigue is different from other forms of fatigue as it is neither caused by increased activity levels nor restored by rest, and is comprised of central (motivational) and peripheral (metabolic and muscle-driven) components [3,5,6]. These “sickness behavior” side effects of chemotherapy persist during and following treatment [3,4] resulting in frequent patient reports of severely decreased quality of life [3]. One common chemotherapeutic drug, paclitaxel, is a taxane agent that binds to microtubules to prevent proper mitotic spindle formation and is a “mainstay” treatment for breast, ovarian, and other cancers (reviewed in [7]). Compared to other chemotherapeutic drugs (e.g., cyclophosphamide [8,9], doxorubicin [8,9], 5-fluorouracil [9,10], methotrexate [11]), the causal role and underlying mechanisms of taxane drugs in physiological and behavioral toxicities is poorly understood.
Systemic inflammation resulting from immune cell signaling triggered by chemotherapy-induced cell death, is posited as a primary contributor to weight loss, anorexia, and fatigue [8]. Taxane drugs, including paclitaxel, are associated with increased circulating concentrations of the pro-inflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in cancer patients and preclinical models [[12], [13], [14]]. Indeed, these paclitaxel-induced increases in peripheral cytokines are significantly correlated with increased fatigue in cancer patients [13,15,16]. Peripheral inflammation can be translated into central inflammation and sickness behaviors through multiple pathways: circulating cytokines can activate endothelial cells and immune cells near more permeable portions (e.g., near circumventricular organs) of the blood-brain barrier, resulting in cytokine release in the brain; peripheral cytokines can activate vagal afferents, leading to neural activation of brain nuclei controlling sickness behavior; and peripheral cytokines leading to prostaglandin E2 production in brain endothelial cells, resulting in prostaglandin-induced fever (reviewed in [17]). However, the temporal dynamics of the onset and duration of paclitaxel-induced sickness behaviors, and the understanding of differences between a single dose versus more clinically-relevant multiple doses is neither well-understood nor well-modeled in the current literature. Centrally-mediated fatigue is difficult to quantify due to the need to distinguish lethargy versus a lack of motivation for locomotion, and methods of assessment have varied in clinical and preclinical studies [13,18]. Thus, a comprehensive analysis of fatigue (passive versus active motivation, central versus peripheral contributions to fatigue) throughout paclitaxel treatment is warranted.
One potential mechanism by which inflammation leads to anorexia and fatigue is through the melanocortin pathway (reviewed in [19] and [20]), however this pathway has not yet been investigated in the context of chemotherapy. In one potential pathway, inflammation arising from paclitaxel treatment increases circulating leptin [21], which activates pro-opiomelanocortin (POMC)-expressing neurons in the arcuate nucleus of the hypothalamus [22] to release α-melanocyte-stimulating hormone (α-MSH). Neurons in the paraventricular nucleus of the hypothalamus are then activated by α-MSH, ultimately resulting in reduced food intake behavior [19,20]. The counterbalance to this pathway occurs by elevated circulating ghrelin, which promotes orexigenic signaling that results in increased food intake (reviewed in [23]). Ghrelin is synthesized in the stomach and is secreted into circulation, where it binds to the growth hormone secretagogue receptor (GHSR) in target tissues. When ghrelin binds to the GHSR on neuropeptide Y (NPY) neurons in the arcuate nucleus, POMC neurons are silenced and food intake is stimulated [23]. Orexigenic neurons have shown to be inhibited by other classes of chemotherapeutic drugs, and in addition to affecting food intake, orexin-A/hypocretin-1 administration reverses fatigue induced by a cocktail of doxorubicin, cyclophosphamide, and 5-fluorouracil chemotherapies [8].
Physical exercise has been investigated as a potential treatment to improve symptoms associated with chemotherapy-induced toxicities in clinical studies [24,25]. Doxorubicin and 5-fluorouracil/methotrexate-induced cognitive deficits [26,27] and decreases in muscle mass in rodent models [2,10,28] have been shown to be ameliorated by exercise. Moreover, physical exercise reduces both central and peripheral inflammation in clinical and preclinical models [29,30], and activates orexin neurons to stimulate food intake [31]. However, the extent to which exercise reverses paclitaxel-induced fatigue, anorexia, and inflammation has not been determined.
In the present study, we examined the effects of paclitaxel chemotherapy in mice over single or multiple doses in order to understand the time course of chemotherapy-induced sickness behaviors and inflammation, including multiple facets of fatigue behavior. We then tested the capacity of exercise, in the form of voluntary wheel running, to ameliorate longitudinal paclitaxel-induced fatigue, anorexia, body mass loss, and their underlying mechanisms. Our aim of the present study was to determine the extent to which paclitaxel increases peripheral inflammation and alters melanocortin signaling, and the extent to which these changes induce murine sickness behaviors.
Section snippets
Mice
Female, 7−8-week-old, nulliparous C57BL/6 mice (Charles River, Wilmington, MA, USA) were acclimated to a 14 h light-10 h dark light cycle (lights on: 0000 EST, lights off: 1400 EST) in a temperature-controlled vivarium (22 ± 1 °C) for one week prior to experiments. Female mice were exclusively used to control for sex differences and to create a more clinically-relevant model for studying the effects of paclitaxel in breast cancer patients. Mice were handled at least 3 times prior to any
Paclitaxel induces sickness behaviors but does not affect locomotor coordination
Mice treated with paclitaxel failed to increase body mass over time from the third dose of chemotherapy (Day 5, Fig. 1B) through five days following the final dose of chemotherapy (Day 16, F1, 38 = 16.69, p <0.05, post-hoc comparisons: p < 0.05 for Days 7, 9, 11, and 14, Fig. 1B). However, food intake remained relatively consistent between groups over time, with an interaction between treatment and time (based on a slight decrease after the first and final paclitaxel doses) and a compensatory
Discussion
The present study thoroughly examined the effects of paclitaxel on sickness behaviors and peripheral and central inflammation in a mouse model and the capacity for voluntary exercise to ameliorate these deleterious effects. While behavioral side effects and toxicities associated with other chemotherapeutics have been extensively studied [2,36], a paucity of information on the commonly-prescribed class of taxanes (e.g., paclitaxel) has limited our understanding of how these drugs specifically
Conclusions
Together, the present study determined a time course of paclitaxel-induced inflammation and sickness behaviors, and identified exercise as a potential measure to protect against paclitaxel-related weight loss via metabolic pathways. These findings provide insight into various causes of paclitaxel-induced sickness behaviors independently of tumors and identifies a possible mechanism of how exercise intervention may improve cancer patient quality of life.
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgements
The authors thank Dr. Michelle Basso, Lesley Fisher, Browning Haynes, Ashley Lahoud, Jasskiran Kaur, Wesley Wang, and Jaimie Gray for their technical assistance. We also thank Dr. Stacey Meeker, Megan Fleming, and Cindy Fairbanks for animal husbandry. We would like to acknowledge the Small Animal Imaging Core at The Ohio State University who provided access and use of the EchoMRI analyzer used in this study. This work was supported by The Ohio State University Medical Center (L.P.), a Pelotonia
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