Abstract
Nucleotide excision repair (NER) and cell cycle checkpoints impact the ability of the anti-cancer drug cisplatin to inhibit cell proliferation and induce cell death. Genetic studies have shown that both NER and cell cycle progression are impacted by the circadian clock, which has emerged as a novel pharmacological target for the treatment of various disease states. In this study, cultured human cell lines were treated with combinations of cisplatin and the circadian clock modulating compounds KS15 and SR8278, which enhance circadian clock transcriptional output by inhibiting the activities of the cryptochrome and REV-ERB proteins, respectively. Treatment of cells with KS15 and SR8278 protected cells against the anti-proliferative effects of cisplatin and increased the expression of NER factor XPA and cell cycle regulators Wee1 and p21 at the mRNA and protein level. Correlated with these molecular changes, KS15 and SR8278 treatment resulted in fewer unrepaired cisplatin–DNA adducts in genomic DNA and a higher fraction of cells in the G1 phase of the cell cycle. Thus, the use of pharmacological agents targeting the circadian clock could be a novel approach to modulate the responses of normal and cancer cells to cisplatin chemotherapy regimens.
Highlights
Cisplatin and other platinating agents are widely used in the treatment of different cancers due to their formation of adducts on DNA that interfere with DNA replication and induce cell death in rapidly proliferating cancer cells[1,2]
A schematic of the circadian clock transcription-translation feedback system is provided in Fig. 1A along with the two clock-modulating compounds (KS15 and SR8278) that were tested in this study due to their documented ability to alter circadian promoter activity and/or clock-control genes (CCGs) expression[22,23,24]
Because the effectiveness of the anti-cancer drug cisplatin is impacted by cellular processes that are regulated by the circadian clock, such as DNA repair and cell cycle checkpoints[18,25], the effect of KS15 and SR8278 on DNA repair, cell cycle progression, and cell viability were tested both alone and in various combinations
Summary
Cisplatin and other platinating agents are widely used in the treatment of different cancers due to their formation of adducts on DNA that interfere with DNA replication and induce cell death in rapidly proliferating cancer cells[1,2]. The circadian clock is composed of a transcription-translation feedback loop in which the CLOCK-BMAL1 heterodimeric protein complex binds to E-box elements in promoters of target clock-control genes (CCGs) to modulate gene expression[8]. Discovery screens have identified compounds that bind to and regulate protein components of the circadian clock machinery[20,21] These small molecules may provide a new way to modulate cell and tissue biology under normal or pathological conditions and in response to external stressors, such as chemotherapy. The purpose of the current study was to examine whether circadian clock-modulating compounds can be used to alter the expression of genes relevant to cisplatin DNA damage responses and control the anti-proliferative effects of this common anti-cancer therapeutic drug in cultured cells in vitro
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