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.
Highlights
Circadian clocks generate 24-hour rhythms of physiology and behavior in most living organisms
The screen used a 126-drug panel that includes a comprehensive set of anticancer compounds targeting multiple signaling pathways such as those involved in cell survival (Raf/Ras and Fgfr/Pdgfr/Vegfr), cell cycle control (Cdk, Plk, Aurk, Wee1, CHK1, and ATM), autophagy, and apoptosis (p53/bcl2/Bimp)
Drugs were delivered at different circadian phases relative to the time of synchronization with dex, and each drug was tested at eight different serial dilutions
Summary
Circadian clocks generate 24-hour rhythms of physiology and behavior in most living organisms. These conserved timing systems are thought to confer the host species with survival benefits by enabling adaptation of physiology with cyclic environmental changes (e.g., light, food availability, and predation). Cell-autonomous rhythms are driven primarily by an autoregulatory feedback loop in which the BMAL1 and CLOCK transcription factor complex cyclically activates transcription of its own repressors, Period (PER)/Cryptochrome (CRY). The core oscillator is complemented by a second loop in which periodic expression of BMAL1 is maintained by the REV-ERB / repressor and ROR / activator proteins [3]. With additional levels of posttranscriptional and posttranslational processing, the molecular clockwork coordinates temporal programs via multiple clock-output genes [4]
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