title: Circadian sensitivity to the chemotherapeutic agent cyclophosphamide depends on the functional status of the CLOCK/BMAL1 transactivation complex.
abstract: The circadian clock controls many aspects of mammalian physiology, including responses to cancer therapy. We find that wild-type and circadian mutant mice demonstrate striking differences in their response to the anticancer drug cyclophosphamide (CY). While the sensitivity of wild-type mice varies greatly, depending on the time of drug administration, Clock mutant and Bmal1 knockout mice are highly sensitive to treatment at all times tested. On the contrary, mice with loss-of-function mutations in Cryptochrome (Cry1-/-Cry2-/- double knockouts) were more resistant to CY compared with their wild-type littermates. Thus, both time-of-day and allelic-dependent variations in response to chemotherapy correlate with the functional status of the circadian CLOCK/BMAL1 transactivation complex. Pharmacokinetic analysis of plasma concentration of different CY metabolites shows that, in contrast to the traditional view, circadian variations in drug sensitivity cannot be attributed to the changes in the rates of CY metabolic activation and/or detoxification. At the same time, mice of different circadian genotypes demonstrate significant differences in B cell responses to toxic CY metabolites: B cell survival/recovery rate was directly correlated with the in vivo drug sensitivity. Based on these results, we propose that the CLOCK/BMAL1 transcriptional complex affects the lethality of chemotherapeutic agents by modulating the survival of the target cells necessary for the viability of the organism.
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
authors.forename: Victoria Y
authors.initials: VY
authors.lastname: Gorbacheva
authors.forename: Roman V
authors.initials: RV
authors.lastname: Kondratov
authors.forename: Renliang
authors.initials: R
authors.lastname: Zhang
authors.forename: Srujana
authors.initials: S
authors.lastname: Cherukuri
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Gudkov
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Takahashi
authors.forename: Marina P
authors.initials: MP
authors.lastname: Antoch
mesh_terms: D056930:ARNTL Transcription Factors; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D002940:Circadian Rhythm; D018920:Coculture Techniques; D003520:Cyclophosphamide / Q000097:blood / Q000494:pharmacology*; D022781:Hepatocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology*
chemical_list: D056930:ARNTL Transcription Factors; D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D003520:Cyclophosphamide; D015534:Trans-Activators; D014157:Transcription Factors; C538961:Bmal1 protein, mouse; C538944:Clock protein, mouse