Paclitaxel chemotherapy disrupts behavioral and molecular circadian clocks in mice.
Antineoplastic
Cancer treatment
Clock genes
Cortex
Corticosterone
Free-running
Hippocampus
Master clock
Suprachiasmatic nucleus (SCN)
Journal
Brain, behavior, and immunity
ISSN: 1090-2139
Titre abrégé: Brain Behav Immun
Pays: Netherlands
ID NLM: 8800478
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
received:
28
06
2021
revised:
07
09
2021
accepted:
18
09
2021
pubmed:
27
9
2021
medline:
15
3
2022
entrez:
26
9
2021
Statut:
ppublish
Résumé
Cancer patients experience circadian rhythm disruptions in activity cycles and cortisol release that correlate with poor quality of life and decreased long-term survival rates. However, the extent to which chemotherapy contributes to altered circadian rhythms is poorly understood. In the present study, we examined the extent to which paclitaxel, a common chemotherapy drug, altered entrained and free-running circadian rhythms in wheel running behavior, circulating corticosterone, and circadian clock gene expression in the brain and adrenal glands of tumor-free mice. Paclitaxel injections delayed voluntary wheel running activity onset in a light-dark cycle (LD) and lengthened the free-running period of locomotion in constant darkness (DD), indicating an effect on inherent suprachiasmatic nucleus (SCN) pacemaker activity. Paclitaxel attenuated clock gene rhythms in multiple brain regions in LD and DD. Furthermore, paclitaxel disrupted circulating corticosterone rhythms in DD by elevating its levels across a 24-hour cycle, which correlated with blunted amplitudes of Arntl, Nr1d1, Per1, and Star rhythms in the adrenal glands. Paclitaxel also shortened SCN slice rhythms, increased the amplitude of adrenal gland oscillations in PER2::luciferase cultures, and increased the concentration of pro-inflammatory cytokines and chemokines released from the SCN. These findings indicate that paclitaxel disrupts clock genes and behavior driven by the SCN, other brain regions, and adrenal glands, which were associated with chemotherapy-induced inflammation. Together, this preclinical work demonstrates that chemotherapy disrupts both central and peripheral circadian rhythms and supports the possibility that targeted circadian realignment therapies may be a novel and non-invasive way to improve patient outcomes after chemotherapy.
Identifiants
pubmed: 34563619
pii: S0889-1591(21)00555-9
doi: 10.1016/j.bbi.2021.09.011
pmc: PMC8671246
mid: NIHMS1745379
pii:
doi:
Substances chimiques
Period Circadian Proteins
0
Paclitaxel
P88XT4IS4D
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
106-118Subventions
Organisme : NIA NIH HHS
ID : R01 AG065830
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA216290
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM133032
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
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