Doxorubicin administration modulates cancer-related fatigue in a time-of-day-dependent manner

Cancer-related fatigue (CRF) is one of the most debilitating long-term consequences of cancer therapy, with limited treatment options. Anthracyclines, such as doxorubicin (Adriamycin), are cornerstone chemotherapeutics but are associated with substantial toxicity, including fatigue. Notably, doxorubicin has been shown to interfere with the circadian system. Whether the timing of anthracycline administration impacts the development of CRF and other toxicities remains unknown. To investigate this, mice (C57BL/6J) were treated with doxorubicin (4x 5 mg/kg) over a 10-day period at different times of day (ZT2, ZT8, ZT14 or ZT20). Fatigue was assessed by monitoring voluntary running wheel and home-cage locomotor activity. Circadian parameters were derived from running wheel activity. Additionally, cardiac toxicity, neuroinflammation, systemic inflammation, grip strength, body weight, and metabolomic and lipidomic profiles were evaluated. Doxorubicin treatment at the early active phase (ZT14) elicited the most severe fatigue. This time effect was paralleled by lower plasma cytokines levels, altered metabolomic and lipidomic plasma profiles, and enhanced microglial activity in the suprachiasmatic nucleus (SCN). No parallel time-of day effects were observed in general welfare or cardiac dysfunction. Our results indicate that fatigue severity in mice varies with drug administration time, with fatigue being most severe following treatment at ZT14. The observed increased microglial phagocytic state in the SCN, suggests that the neuroimmune response of this hypothalamic region is critical for developing fatigue. Our findings support the development of time-adjusted anthracycline regimens to improve quality of life of cancer patients and survivors.