Files and links (1)
CC BY V4.0, Open Access
Journal article
Time-of-day specificity of anticancer drugs may be mediated by circadian regulation of the cell cycle
Science advances, Vol.7(7), eabd2645
02/12/2021
PMID: 33579708
Abstract
Circadian rhythms are an integral part of physiology, underscoring their relevance for the treatment of disease. We conducted cell-based high-throughput screening to investigate time-of-day influences on the activity of known antitumor agents and found that many compounds exhibit daily rhythms of cytotoxicity concomitant with previously reported oscillations of target genes. Rhythmic action of HSP90 inhibitors was mediated by specific isoforms of HSP90, genetic perturbation of which affected the cell cycle. Furthermore, clock mutants affected the cell cycle in parallel with abrogating rhythms of cytotoxicity, and pharmacological inhibition of the cell cycle also eliminated rhythmic drug effects. An HSP90 inhibitor reduced growth rate of a mouse melanoma in a time-of-day-specific manner, but efficacy was impaired in clock-deficient tumors. These results provide a powerful rationale for appropriate daily timing of anticancer drugs and suggest circadian regulation of the cell cycle within the tumor as an underlying mechanism.
Metrics
1 Record Views
Details
- Title
- Time-of-day specificity of anticancer drugs may be mediated by circadian regulation of the cell cycle
- Creators
- Yool Lee - Washington State University, Biomedical Sciences, Department ofShi Yi Fong - Howard Hughes Medical InstituteJoy Shon - Howard Hughes Medical InstituteShirley L Zhang - Howard Hughes Medical InstituteRebekah Brooks - The Wistar InstituteNicholas F Lahens - Translational TherapeuticsDechun Chen - Howard Hughes Medical InstituteChi Van Dang - Johns Hopkins UniversityJeffrey M Field - Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAAmita Sehgal - University of Pennsylvania
- Publication Details
- Science advances, Vol.7(7), eabd2645
- Academic Unit
- Elson S. Floyd College of Medicine
- Grant note
- R01 CA057341 / NCI NIH HHS K99 HL147212 / NHLBI NIH HHS R01 HL134923 / NHLBI NIH HHS R37 NS048471 / NINDS NIH HHS F31 CA232551 / NCI NIH HHS P30 CA010815 / NCI NIH HHS R01 CA051497 / NCI NIH HHS
- Identifiers
- 99901132536001842
- Language
- English
- Resource Type
- Journal article