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

Abstract

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.

Circadian Clocks and Metabolism

“…Indeed, treatment of human U20S cells stably expressing a Bmal1-Luc reporter construct with more than 120,000 potential drugs uncovered numerous compounds that either shorten or lengthen the period, including various inhibitors of CKIδ, CKIε, and GSK-3 (Hirota and Kay 2009; Hirota et al 2008). This novel approach provides a means to pharmacologically control the circadian cycle, which may be useful in the treatment of circadian disorders and metabolic disturbances with a circadian component (reviewed in Antoch and Kondratov 2013). It also offers new insight into the interaction of previously unsuspected pathways with the circadian system.…”

The Small Molecule Nobiletin Targets the Molecular Oscillator to Enhance Circadian Rhythms and Protect against Metabolic Syndrome

“…Recent studies have explored the strategy of directly manipulating circadian rhythms to ameliorate the metabolic syndrome (Antoch and Kondratov, 2013; Chen et al, 2013; Farrow et al, 2012; Schroeder and Colwell, 2013). For example, time-restricted intake of high-fat diet (HFD) was shown to protect mice against metabolic disease (Hatori et al, 2012).…”

Circadian rhythms and new options for novel anticancer therapies

“…The circadian clock regulates the normal cell cycle and apoptosis, 38 and anticancer drugs usually target different stages of the cell cycle, so differences in the cell cycle in cancerous versus healthy cells represent the rationale of anticancer chronotherapy. 39 In mice and rats, rhythm in tolerance of many anticancer drugs was shown: cytokines, cytostatics, antiangiogenic agents, cell cycle inhibitors, etc.…”