Circadian Clock Manipulation for Cancer Prevention and Control and the Relief of Cancer Symptoms

Abstract

Life has evolved on this planet with regular daily spans of direct solar energy availability alternating with nocturnal spans of dark. Virtually every earth-borne life form has factored this circadian pattern into its biology to ensure the temporal coordination with its resonating environment, a task essential for its individual survival and that of its species. The first whole genome inspections of mutations in human colon and breast cancer have observed specific retained clock gene mutations. Single nucleotide polymorphisms within the genes of clock, clock-controlled, and melatonin pathways have been found to confer excess cancer risk or protection from cancer. Experimental studies have shown that specific core clock genes (Per2 and Per1) are tumor suppressors because their genetic absence doubles tumor numbers, and decreasing their expression in cancer cells doubles cancer growth rate, whereas their overexpression decreases cancer growth rate and diminishes tumor numbers. Experimental interference with circadian clock function increases cancer growth rate, and clinical circadian disruption is associated with higher cancer incidence, faster cancer progression, and shorter cancer patient survival. Patients with advanced lung cancer suffering greater circadian activity/sleep cycle disruption suffer greater interference with function, greater anxiety and depression, poorer nighttime sleep, greater daytime fatigue, and poorer quality of life than comparable patients who maintain good circadian integration. We must now determine whether strategies known to help synchronize the circadian clocks of normal individuals can do so in advanced cancer patients and whether doing so allows cancer patients to feel better and/or live longer. Several academic laboratories and at least 2 large pharmaceutical firms are screening for small molecules targeting the circadian clock to stabilize its phase and enhance its amplitude and thereby consolidate and coordinate circadian organization, which in turn is likely to help prevent and control human cancer. These drugs and strategies can, in turn, be used to make cancer patients with advanced disease feel and function more normally.

Melatonin decreases cell proliferation, impairs myogenic differentiation and triggers apoptotic cell death in rhabdomyosarcoma cell lines

“…Notably, previous findings have shown a role for melatonin in preventing tumor initiation and progression (28)(29)(30)(31)(32)(33)(34). Specifically, melatonin was reported to inhibit cell proliferation and induce apoptosis in osteosarcoma (35), B-lymphoma (36) and colorectal cancer cells (37), as well as to decrease the weight of tumor masses in breast and prostate cancer (38)(39)(40).…”

Circadian clocks and cell division

“…6,52 Nevertheless, several groups continue to avidly search for practical and efficacious chronochemotherapeutic regimes. 21,37,53 Is the Circadian Pacemaker a Transcription/Translation Feedback Loop?…”

Melatonin action in tumor skeletal muscle cells: an ultrastructural study

“…Since then, this pineal neurohormone Mel has been repeatedly described as a potential anti-cancer molecular tool given its demonstrated pro-apoptotic effect and oncostatic action towards different cancer cell lines (Bizzarri et al, 2013;Perdomo et al, 2013;Rodriguez et al, 2013;Hong et al, 2014), therefore contributing to cancer protection (Hrushesky et al, 2009;Mao et al, 2010;Bukowska, 2011;Santoro et al, 2012).…”