Pharmacological modulators of the circadian clock as potential therapeutic drugs

Antoch, Marina P.; Chernov, Mikhail V.

doi:10.1016/j.mrgentox.2009.07.015

Cited by 15 publications

(13 citation statements)

References 75 publications

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“…To identify small molecules capable of modulating CLOCK/BMAL1 activity, we designed a readout system based on mouse fibrosarcoma L929 cells expressing high levels of endogenous CLOCK and BMAL1, positive regulators circadian transcriptional machinery, transduced with Per1 -driven luciferase reporter construct (L929- Per1 ) [18]. By screening a chemical library of known pharmacological agents (LOPAC, Sigma, 1280 compounds total) in this system, we identified 14 inhibitors and 17 activators of Per1 promoter as our major hits (Supplementary Tables 1 and 2).…”

Section: Resultsmentioning

confidence: 99%

“…Screening conditions were optimized by testing the assay for temporal and spatial signal variability using several 96-well plates as described in [18]. Luciferase readings of untreated cells (constant high luciferase signal) and cells treated with Actinomycin D (background signal) were used to calculate Z-factor using the equation:

Z = 1 - \frac{(3 δ s + 3 δ c)}{| μ s - μ c |}

[49].…”

Section: Methodsmentioning

confidence: 99%

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Selenium is a modulator of circadian clock that protects mice from the toxicity of a chemotherapeutic drug via upregulation of the core clock protein, BMAL1

Spengler

Kuropatwinski

et al. 2011

Oncotarget

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Selenium compounds are known as cancer preventive agents and are also able to ameliorate the toxicity associated with anti-cancer radiation and chemotherapy in mouse models. Sensitivity to the toxicity of chemotherapy is also modulated by the circadian clock, molecular time-keeping system that underlie daily fluctuations in multiple physiological and biochemical processes. Here we show that these two mechanisms are interconnected. By screening a library of small molecules in a cell-based reporter system, we identified L-methyl-selenocysteine as a positive regulator of the core clock protein, BMAL1. L-methyl-selenocysteine up-regulates BMAL1 at the transcriptional level both in cultured cells and in mice. We also show that in tissue culture selenium exerts its action by interfering with TIEG1-mediated repression of Bmal1 promoter. Selenium treatment fails to protect BMAL1-deficient mice from toxicity induced by the chemotherapeutic agent cyclophosphamide but does protect Clock mutant mice deficient in circadian rhythm control but having normal BMAL1. These findings define selenium as circadian modulator and indicate that the tissue protective effect of selenium results, at least in part, from up-regulation of BMAL1 expression and subsequent enhancement of CLOCK/BMAL1-mediated transcription.

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Section: Resultsmentioning

confidence: 99%

Z = 1 - \frac{(3 δ s + 3 δ c)}{| μ s - μ c |}

[49].…”

Section: Methodsmentioning

confidence: 99%

Selenium is a modulator of circadian clock that protects mice from the toxicity of a chemotherapeutic drug via upregulation of the core clock protein, BMAL1

Spengler

Kuropatwinski

et al. 2011

Oncotarget

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“…So, screening approach is performed to introduce modern small molecules capable of pharmacological modulation of the molecular clock to control these pathological situations. 48 The evidence for the availability and impact of this approach is still under investigations for both academic and clinical purposes.…”

Section: Chronopharmacodynamics and Molecular Clockmentioning

confidence: 99%

Molecular Basis of Chronopharmaceutics

Ohdo

Koyanagi

Matsumoto

et al. 2011

Journal of Pharmaceutical Sciences

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“…Two commercially available libraries, LOPAC (Sigma, 1200 compounds) and Spectrum (library of 2000 natural compounds, MicroSource Discovery, Inc), were used to screen for activators and inhibitors of CLOCK/BMAL1-mediated expression of Per1 gene (Antoch and Chernov 2009). Importantly, this screen identified several known regulators of circadian function such as glucocorticoids, 2-methoxyestradiol, forskolin, PKC and p38 MAPK inhibitors as well as some hits identified by circadian-driven approach (Hirota et al 2008), all of which validated the feasibility of the approach.…”

Section: Search For Pharmacological Modulators Of Circadian Clock By mentioning

confidence: 99%

Pharmacological Modulators of the Circadian Clock as Potential Therapeutic Drugs: Focus on Genotoxic/Anticancer Therapy

Antoch

Kondratov

2013

Circadian Clocks

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The circadian clock is an evolutionary conserved intrinsic time-keeping mechanism that controls daily variations in multiple biological processes. One important process that is modulated by the circadian clock is an organism’s response to genotoxic stress, such as that induced by anticancer drug and radiation treatments. Numerous observations made in animal models have convincingly demonstrated that drug-induced toxicity display prominent daily variations, therefore undesirable side effects could be significantly reduced by administration of drugs at specific times when they are better tolerated. In some cases, these critical times of the day coincide with increased sensitivity of tumor cells allowing for a greater therapeutic index. Despite encouraging results of chronomodulated therapies, our knowledge of molecular mechanisms underlying these observations remains sketchy. Here we review recent progress in deciphering mechanistic links between circadian and stress response pathways with a focus on how these findings could be applied to anticancer clinical practice. We discuss the potential for using high throughput screen to identify small molecules that can modulate basic parameters of the entire circadian machinery as well as functional activity of its individual components. We also describe the discovery of several small molecules that can pharmacologically modulate clock and that have a potential to be developed into therapeutic drugs. We believe that translational applications of clock-targeting pharmaceuticals are two-fold: they may be developed into drugs to treat circadian-related disorders or used in combination with existing therapeutic strategies to improve therapeutic index of a given genotoxic treatment via the intrinsic clock mechanism.

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Pharmacological modulators of the circadian clock as potential therapeutic drugs

Cited by 15 publications

References 75 publications

Selenium is a modulator of circadian clock that protects mice from the toxicity of a chemotherapeutic drug via upregulation of the core clock protein, BMAL1

Selenium is a modulator of circadian clock that protects mice from the toxicity of a chemotherapeutic drug via upregulation of the core clock protein, BMAL1

Molecular Basis of Chronopharmaceutics

Pharmacological Modulators of the Circadian Clock as Potential Therapeutic Drugs: Focus on Genotoxic/Anticancer Therapy

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