Circadian Timing in Cancer Treatment: The Biological Foundation for an Integrative Approach

Lis, Christopher G.; Grutsch, James F.; Wood, Patricia A.; You, Mark; Rich, Ivan N.; Hrushesky, William J. M.

doi:10.1177/1534735403002002002

Cited by 45 publications

(29 citation statements)

References 27 publications

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“…Because cytokines that are produced by lymphocytes and macrophages are potent mediators of immune responses and the levels of individual cytokines can determine immune effector mechanisms, understanding immune-circadian clock control of specific immune mechanisms may have important clinical applications, such as optimization of the treatment of patients with septic shock, autoimmune diseases, and hematological diseases. As the toxicity and the antitumor efficiency of many traditional cytotoxic drugs in cancer therapy vary significantly with the time of day of drug administration (23), analysis of the circadian organization of physiological immune function not only might provide a better insight into the immune system in general, but also might offer a reduction in bone marrow toxicity and an increased intensity and improved efficiency of cytotoxic drugs for cancer patients.…”

Section: Vol 74 2006mentioning

confidence: 99%

The Circadian ClockPeriod 2Gene Regulates Gamma Interferon Production of NK Cells in Host Response to Lipopolysaccharide-Induced Endotoxic Shock

Liu¹,

Mankani

Shi³

et al. 2006

Infect Immun

202

102

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The Period 2 (Per2) gene is a key molecular component in controlling mammalian circadian rhythms at the levels of gene expression, physiology, and pathogenesis. Although many immune parameters, such as the number of different subtypes of circulating immune cells and the level of cytokine production in response to infection with bacteria and viruses, have been well documented to display a circadian pattern in mammals, the basic features of molecular clock components in the immune system and the role of clock genes in regulating host immune defenses remain uncharacterized. Previously, we have reported that circadian clock genes oscillate in human mononuclear cells. Here we report that Per2-deficient mice were more resistant to lipopolysaccharide (LPS)-induced endotoxic shock than control wild-type mice. We further demonstrate that the levels of the proinflammatory cytokines gamma interferon (IFN-␥) and interleukin-1␤ (IL-1␤) in the serum were dramatically decreased in Per2 ؊/؊ mice following LPS challenge, while production of tumor necrosis factor alpha, IL-6, and IL-10 was approximately normal, compared to that in control wild-type mice. Flow cytometric analyses confirmed that the cellularity of most of the immune cell subsets in the spleens of LPS-challenged mice was normal and that the impaired IFN-␥ production in Per2 ؊/؊ mice was attributable to defective NK and NKT cell function. Our data suggest that Per2 is an important regulator of NK cell function, therefore providing the first direct link between the circadian clock system and innate immune responses.Circadian rhythms are daily oscillations of multiple biological processes driven by endogenous clocks. The master circadian clock in mammals resides in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. The endogenous clock is further distinguished by its ability to be entrained to a new day/night regimen by environmental cues such as light and temperature cycles (13,27,29). It was originally thought that the mammalian circadian clock system was hierarchically organized; however, while the SCN is a master circadian clock tissue, generating self-sustained circadian oscillators which determine the pace and amplitude of the expression of the circadian clock genes in peripheral tissues through neuronal and hormonal signals, these peripheral clocks in turn control the output of circadian physiology and behavior. However, the details of how the SCNЈs signaling pathway controls the peripheral clock still remain to be elucidated.Circadian rhythms are known to influence the immune response of mammals through their effects on the circulation of the blood as related to diurnal sleeping/waking and activity cycles. Born and coworkers (6) demonstrated that in humans, blood cell compartmentalization, such as with peripheral cell counts of neutrophils, T-lymphocyte subsets, B lymphocytes, monocytes, and natural killer (NK) cells, displays a circadian fluctuation across the day. The peak of each subtype of cells in peripheral blood varies with time. The numbers...

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Section: Vol 74 2006mentioning

confidence: 99%

The Circadian ClockPeriod 2Gene Regulates Gamma Interferon Production of NK Cells in Host Response to Lipopolysaccharide-Induced Endotoxic Shock

Liu¹,

Mankani

Shi³

et al. 2006

Infect Immun

202

102

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“…These rhythms have direct and indirect implications for human heath. The metabolism and efficacy of drugs depends considerably on the time of day they are administered (Antoch et al, 2005;Halberg et al, 2006;Lis et al, 2003). Moreover, disruptions of the circadian clock have been shown to increase susceptibility to cancer, heart disease, and metabolic disorders while directly causing serious sleep disorders and influencing mental illness (Curtis and Fitzgerald, 2006;Halberg et al, 2006;Klerman, 2005;Levi and Schibler, 2007).…”

Section: Introductionmentioning

confidence: 99%

High-resolution Time Course Analysis of Gene Expression from Pituitary

Hughes

DeHaro²,

Pulivarthy³

et al. 2007

Cold Spring Harbor Symposia on Quantitative Biology

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In both the suprachiasmatic nucleus and peripheral tissues, the circadian oscillator drives rhythmic transcription of downstream target genes. Recently, a number of studies have used DNA microarrays to systematically identify oscillating transcripts in plants, fruit flies, rats and mice. These studies have identified several dozen to many hundred rhythmically expressed genes by sampling tissues every four hours for one, two, or more days. To extend this work, we have performed DNA microarray analysis on RNA derived from the mouse pituitary sampled every hour for two days. COSOPT and Fisher's G-test were employed at a false-discovery rate less than 5% to identify more than 250 genes in the pituitary that oscillate with a 24-hour period length. We found that increasing the frequency of sampling across the circadian day dramatically increased the statistical power of both COSOPT and Fisher's G-test, resulting in considerably more high-confidence identifications of rhythmic transcripts than previously described. Finally, to extend the utility of these data sets, a web-based resource has been constructed at http://wasabi.itmat.upenn.edu/circa/mouse that is freely available to the research community.

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“…For example, in cancer therapy, the circadian rhythms of metabolic enzymes and signal transduction proteins targeted by antitumor drugs influence the effect of these drugs (9)(10)(11). It has been suggested that administration of drugs at an appropriate time of the day could improve the outcome of pharmacotherapy.…”

Section: Introductionmentioning

confidence: 99%

Circadian Regulation of mTOR by the Ubiquitin Pathway in Renal Cell Carcinoma

et al. 2014

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Circadian clock systems regulate many biologic functions, including cell division and hormone secretion in mammals. In this study, we explored the effects of circadian control on the pivot cell growth regulatory mTOR, the activity of which is deregulated in tumor cells compared with normal cells. Specifically, we investigated whether the antitumor effect of an mTOR inhibitor could be improved by changing its dosing schedule in RenCa tumorbearing mice. Active, phosphorylated mTOR displayed a 24-hour rhythm, and levels of total mTOR protein (but not mRNA) also showed a circadian rhythm in RenCa tumor masses. Through investigations of the oscillation mechanism for mTOR expression, we identified the ubiquitination factor Fbxw7 as an mTOR regulator that oscillated in its expression in a manner opposite from mTOR. Fbxw7 transcription was regulated by the circadian regulator D-site-binding protein. Notably, administration of the mTOR inhibitor everolimus during periods of elevated mTOR improved survival in tumor-bearing mice. Our findings demonstrate that the circadian oscillation of mTOR activity is regulated by circadian clock systems, which influence the antitumor effect of mTOR inhibitors. Cancer Res; 74(2); 543-51. Ó2013 AACR.

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Circadian Timing in Cancer Treatment: The Biological Foundation for an Integrative Approach

Cited by 45 publications

References 27 publications

The Circadian ClockPeriod 2Gene Regulates Gamma Interferon Production of NK Cells in Host Response to Lipopolysaccharide-Induced Endotoxic Shock

The Circadian ClockPeriod 2Gene Regulates Gamma Interferon Production of NK Cells in Host Response to Lipopolysaccharide-Induced Endotoxic Shock

High-resolution Time Course Analysis of Gene Expression from Pituitary

Circadian Regulation of mTOR by the Ubiquitin Pathway in Renal Cell Carcinoma

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