Paclitaxel disrupted the molecular and behavioral function of the master circadian clock in female mice.
Evidence
A repeated-chemotherapy mouse study measured clock-gene rhythms, wheel-running responses to jet-lag paradigms, and a phase-response curve, finding abolished or damped transcription and blunted light-induced phase-delay shifts.
Caveat
The findings come from female mice and circadian assays, so they do not establish how much SCN disruption drives circadian symptoms in cancer patients.
Simplified
Cancer patients experience disruptions during and after chemotherapy that can contribute to debilitating side effects. It is unknown how chemotherapy mediates circadian disruptions and specifically the extent to which these disruptions occur at the level of the principal clock, the (SCN) of the hypothalamus. In the present study, we assessed how the commonly used chemotherapeutic, paclitaxel, impacts the SCN molecular clock and SCN-dependent behavioral adaptations to circadian challenges in female mice. Following a repeated chemotherapy regimen, we measured rhythmic SCN expression of molecular clock and circadian-associated transcripts. Paclitaxel chemotherapy disrupted the SCN molecular clock through abolished rhythmicity (,) and damped rhythmic transcription (,,,) of key molecular clock genes. We further determined chemotherapy-induced changes to SCN function by measuring circadian wheel running adaptations to a jet lag phase-delay or phase-advance paradigm and by generating a phase response curve (PRC). Chemotherapy did not alter re-entrainment to a 6 h phase-advance, but after a 6 h phase-delay, chemotherapy-treated mice had a more stable and robust circadian rhythm than vehicle-treated mice, possibly indicative of a weakened or decoupled SCN. In the PRC, chemotherapy blunted light-induced phase-shift delays during subjective night compared with vehicle controls, also indicative of disrupted SCN-dependent entrainment. Together, this work demonstrates that paclitaxel chemotherapy disrupts both the molecular clock and functional re-entrainment of the SCN that could cause or contribute to observed circadian rhythm disruptions after treatment. This research could help guide application of circadian-mediated therapies to mitigate side effects of chemotherapy. Bmal1Nr1d2Ciart Dbp Nr1d1Per2
Key numbers
8
Unique Rhythmically Expressed Genes
Unique genes rhythmically expressed in chemotherapy-treated mice
12
Unique Rhythmically Expressed Genes in
Unique genes rhythmically expressed in -treated mice
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Circadian Biology