Chronotherapeutics for Solid Tumors

Abstract

Circadian rhythms are internal manifestations of the 24-h solar day that allow for synchronization of biological and behavioral processes to the external solar day. This precise regulation of physiology and behavior improves adaptive function and survival. Chronotherapy takes advantage of circadian rhythms in physiological processes to optimize the timing of drug administration to achieve maximal therapeutic efficacy and minimize negative side effects. Chronotherapy for cancer treatment was first demonstrated to be beneficial more than five decades ago and has favorable effects across diverse cancer types. However, implementation of chronotherapy in clinic remains limited. The present review examines the evidence for chronotherapeutic treatment for solid tumors. Specifically, studies examining chrono-chemotherapy, chrono-radiotherapy, and alternative chronotherapeutics (e.g., hormone therapy, TKIs, antiangiogenic therapy, immunotherapy) are discussed. In addition, we propose areas of needed research and identify challenges in the field that remain to be addressed.

Keywords: cancer; chemotherapy; chronotherapy; circadian rhythms; immunotherapy; radiotherapy.

Figure 1

Light is the primary zeitgeber for entrainment to a 24 h cycle in mammals. Solar blue light (~480 nm) excites melanopsin, which in turn activates intrinsically photoreceptive retinal ganglion cells (ipRGCs) that send excitatory signals to the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. Termed the central pacemaker, the SCN dictates daily oscillations in peripheral organs. Created with Biorender.com accessed on 24 July 2023.

Figure 2

The molecular clock is regulated by transcription–translation feedback loops. CLOCK/BMAL1 heterodimerize, translocate to the nucleus, and regulate expression of Per/Cry genes. PER/CRY proteins accumulate in the cytoplasm where they heterodimerize and translocate to the nucleus to inhibit CLOCK/BMAL1-driven promotion of their transcription (top). The CLOCK/BMAL1 heterodimer drives expression of ROR and REV-ERB proteins. ROR and REV-ERB proteins translocate to the nucleus and either drive or inhibit BMAL1 expression, respectively (bottom). Created with Biorender.com accessed on 24 July 2023.