Abstract
5 fluorouracil (5FU) has been a first-choice chemotherapy drug for several cancer types (e.g., colon, breast, head, and neck); however, its efficacy is diminished by patient acquired resistance and pervasive side effects. Leukopenia is a hallmark of 5FU; however, the impact of 5FU-induced leukopenia on healthy tissue is only becoming unearthed. Recently, skeletal muscle has been shown to be impacted by 5FU in clinical and preclinical settings and weakness and fatigue remain among the most consistent complaints in cancer patients undergoing chemotherapy. Monocytes, or more specifically macrophages, are the predominate immune cell in skeletal muscle which regulate turnover and homeostasis through removal of damaged or old materials as well as coordinate skeletal muscle repair and remodeling. Whether 5FU-induced leukopenia extends beyond circulation to impact resident and infiltrating skeletal muscle immune cells has not been examined. The purpose of the study was to examine the acute effects of 5FU on resident and infiltrating skeletal muscle monocytes and inflammatory mediators. Male C57BL/6 mice were given a physiologically translatable dose (35 mg/kg) of 5FU, or PBS, i.p. once daily for 5 days to recapitulate 1 dosing cycle. Our results demonstrate that 5FU reduced circulating leukocytes, erythrocytes, and thrombocytes while inducing significant body weight loss (>5%). Flow cytometry analysis of the skeletal muscle indicated a reduction in total CD45+ immune cells with a corresponding decrease in total CD45+CD11b+ monocytes. There was a strong relationship between circulating leukocytes and skeletal muscle CD45+ immune cells. Skeletal muscle Ly6cHigh activated monocytes and M1-like macrophages were reduced with 5FU treatment while total M2-like CD206+CD11c- macrophages were unchanged. Interestingly, 5FU reduced bone marrow CD45+ immune cells and CD45+CD11b+ monocytes. Our results demonstrate that 5FU induced body weight loss and decreased skeletal muscle CD45+ immune cells in association with a reduction in infiltrating Ly6cHigh monocytes. Interestingly, the loss of skeletal muscle immune cells occurred with bone marrow cell cycle arrest. Together our results highlight that skeletal muscle is sensitive to 5FU’s off-target effects which disrupts both circulating and skeletal muscle immune cells.
Highlights
The increase in 5-year survival rate among cancer patients has increased focus on quality of life to improve patient outcomes (Curt et al, 2000)
Our results extend previous studies to identify that 1 cycle of a clinically translatable dose of 5 fluorouracil (5FU) significantly reduced CD45+ immune cells and infiltrating/activated CD11b+Ly6CHigh monocytes in skeletal muscle that was associated with a decrease in select skeletal muscle inflammatory mediators
Regardless, our results demonstrate that the relative phenotype of skeletal muscle macrophages is not changed by 5FU treatment; the total number of M1-like (CD11c+CD206-), M0-like (CD11c-CD206-), and M1-M2-like transitional macrophages were reduced with 5FU while M2like macrophages appear spared from 5FU’s cytotoxicity – at least following 1 week of 5FU
Summary
The increase in 5-year survival rate among cancer patients has increased focus on quality of life to improve patient outcomes (Curt et al, 2000). There are no Food and Drug Administration approved therapies for chemotherapy-induced cachexia despite the importance of skeletal muscle and lean mass in sustaining 5FU’s therapeutic efficacy and patient quality of life (Sandini et al, 2018; Williams et al, 2018). This is not entirely surprising given that very little is known about the mechanisms responsible for 5FU-induced skeletal muscle dysfunction. Identifying the factors driving chemotherapy-induced skeletal muscle dysfunction is critical to developing effective interventional therapies
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