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 and͞or detoxification. At the same time, mice of different circadian genotypes demonstrate significant differences in B cell responses to toxic CY metabolites: B cell survival͞recovery rate was directly correlated with the in vivo drug sensitivity. Based on these results, we propose that the CLOCK͞BMAL1 transcriptional complex affects the lethality of chemotherapeutic agents by modulating the survival of the target cells necessary for the viability of the organism.chemotherapy ͉ circadian clock ͉ drug response A broad range of organisms from bacteria to animals display circadian oscillations in metabolism, cell proliferation, physiology, and behavior. Circadian rhythms are generated by an intracellular clock mechanism that involves a network of transcriptional feedback loops that drive rhythmic RNA and protein expression of key clock components (reviewed in refs.

Clock and ATF4 transcription system regulates drug resistance in human cancer cell lines

“…Clock has been identified as a protein with regulating function of circadian rhythmicity, which is primary through actions at suprachiasmatic nucleus and the supraoptic nucleus (Moore, 1997). The systemic circadian rhythm is known to be important for the clinical treatment of cancer patients (Canaple et al, 2003;Gorbacheva et al, 2005), and our results imply that cellular rhythm can modulate cellular sensitivity to anticancer agents. Further study is required to prove the fundamental issue how cellular rhythm at a single cell level contributes to systemic chemotherapy.…”

Pharmacological modulators of the circadian clock as potential therapeutic drugs

“…Consistently, wild-type animals show daily variations in their response, which correlates with normal daily variation of the CLOCK/BMAL transcriptional activity. The data suggest that the CLOCK/BMAL1 complex may directly control the molecular determinants of drug sensitivity at the transcriptional level [62]. Importantly, daily fluctuations in CLOCK/BMAL1-dependent transactivation might provide mechanistic explanation for numerous examples of advantages of timed administration of chemotherapeutic drugs compared to conventional methods of delivery (reviewed in [63]).…”

Even a stopped clock tells the right time twice a day: circadian timekeeping in Drosophila

“…In addition to controlling the timing of sleep/wake cycles and thus influencing alertness, circadian clocks in mammals have been shown to control rates of drug detoxification, bone growth, liver regeneration and cell division [3][4][5]. Circadian rhythm disruptions can lead to depression, obesity and higher incidences of cancer [6][7][8][9][10] while normal rhythms control the sensitivity of an organism to drugs of abuse [11][12][13].…”