Dexamethasone exacerbates cytotoxic chemotherapy induced lethargy and weight loss in female tumor free mice

Abstract

Cytotoxic chemotherapy can induce a systemic inflammatory response which has been proposed to be an underlying mechanism of cancer treatment related fatigue. Dexamethasone, a synthetic glucocorticoid that has potent anti-inflammatory effects, is incorporated into chemotherapy regimens to prevent chemotherapy-induced nausea and vomiting (CINV). The purpose of this study was to determine whether by suppressing cytotoxic chemotherapy-induced inflammation, dexamethasone could ameliorate chemotherapy induced fatigue/lethargy in tumor free mice. The effect of dexamethasone (DEX) on Cytoxan-Adriamycin (CA)-induced inflammation was assessed by measuring circulating levels of IL-1β, TNF-α, IL-6, GCSF, KC, and MCP-1 twenty-four-hours post CA injection. Decline in voluntary wheel running activity (VWRA) from baseline (used as a proxy for fatigue/lethargy), body weight and composition, and food intake were monitored in mice administered four cycles of CA every two weeks with or without DEX. CA increased circulating levels of IL-6, GCSF, KC, and MCP-1 and caused a rapid decline in VWRA and body weight immediately following CA-injection. Although the acute CA-induced decline in VWRA and body weight was not evident in mice administered CA + DEX, DEX alone had a suppressive effect on VWRA, and body weight continued to decline in mice administered both CA and DEX while it returned to baseline in CA-treated mice. CA or DEX alone had no long term impact on VWRA but DEX exacerbated lethargy and weight loss in CA-treated mice. Despite dampening the systemic inflammatory response to chemotherapy, dexamethasone failed to ameliorate acute or long term chemotherapy related fatigue/lethargy. Our pre-clinical findings suggest that supportive therapies like dexamethasone used to acutely control nausea and vomiting in cancer patients may actually contribute to overall symptom burden in cancer patients.

Cardioprotective Effect of Croton macrostachyus Stem Bark Extract and Solvent Fractions on Cyclophosphamide‐Induced Cardiotoxicity in Rats

“…In cardioprotective studies, the administration of cyclophosphamide caused a significant body weight loss compared with the normal group. is effect was consistent with previous studies [45][46][47]. is might be due to anorexia as a result of the damaging effect of cyclophosphamide on the gastrointestinal tract or on the appetite center (ventromedial nucleus and lateral hypothalamus) in the hypothalamus [24,48].…”

Comparing passive measures of fatigue-like behavior in mice

“…When evaluating fatigue-like behavior, investigators may find “time active” to be the more stable measure on a daily basis, particularly when looking at 1-minute intervals like we did. This idea may be supported by recent results testing chemotherapy-related fatigue, in which the time on the running wheel may appear to be more stable 14 , though calculated wheel time using 1-hour intervals. However, another study looking at post-exercise fatigue did not appear to find much difference between the two measures 21 .…”

“…In clinical studies, fatigue is typically determined by self-reports and questionnaires, and rarely using behavioral or physical measurements 2 . In contrast, with preclinical mouse models investigators have published quite a few behavioral measures of physical activity to measure fatigue, including: running wheels 7 – 9 , 11 , 12 , 14 – 17 , 20 , 21 ; home cage monitoring using video 7 , 8 , 18 , telemetry 11 , or cages with light beams/sensors 20 ; treadmills 10 , 19 , 21 ; forced swim 8 , 9 ; and open field 12 . However, there are no standards for which methods should be considered reliable indicators of fatigue.…”

Effects of dexamethasone on C6 cell proliferation, migration and invasion through the upregulation of AQP1

“…Studies have indicated that Dex can inhibit the proliferation of a variety of cancer cell lines ( 29 , 30 ). Dex also inhibits the proliferation of Chinese hamster ovary cells, HeLa S3 cervical cancer cells, and the human ovarian cancer cell line 3AO ( 8 ).…”