Effects of exogenous melatonin and circadian synchronization on tumor progression in melanoma‐bearing C57BL6 mice

Abstract

Circadian rhythmicity impairment reportedly becomes significant as a tumor progresses, while the incidence of cancer can be affected by disruption of the circadian system. Melatonin has oncostatic effects on several types of cancer (breast, prostate, and colorectal cancers), while it can be self-defeating in others, such as lymphoma. Melanoma is one of the most aggressive cancers in humans; however, it seems to respond positively to melatonin in vitro. The present work tested whether body temperature (BT) rhythms are impaired by tumor progression, and whether exogenous melatonin restricts tumor growth and restores circadian rhythmicity; therefore, enhancing survival. To this end, C57 mice were intraperitoneal implanted with a temperature data logger and subcutaneously inoculated with melanoma cells. Animals were then submitted to light-dark (LD) 12:12 cycles or continuous light (LL), with or without melatonin administration. Under LD light conditions, the BT rhythm exhibited a marked reduction in the first circadian harmonic amplitude, and increased phase instability (Rayleigh vector) as the tumor progressed. Melatonin administration (2 mg/kg BW/day), on the other hand, increased the BT rhythm amplitude and phase stability, reduced tumor weight and prevented intraperitoneal dissemination. Exposure to LL induced a free-running rhythm (1500 min), significantly increasing tumor malignity, and therefore reducing survival. Surprisingly, the highest tumor weights and morbidity by metastasis were seen in the LL group treated with melatonin probably because this indoleamine was being administered at different subjective hours to free-running animals. Circadian rhythmicity can thus be used as a marker rhythm for tumor progression, as rhythm impairment increases along with tumor malignancy. While melatonin administration improves rhythmicity and enhances survival under LD conditions, the results are self-defeating when they coexist with circadian disruption as it occurs under LL. This emphasizes the importance of taking into account endogenous rhythmicity and limiting melatonin administration to the subjective night in order to restrict melanoma progression.

Involvement of melatonin in autophagy-mediated mouse hepatoma H22 cell survival

“…It has been demonstrated that autophagy is activated by some anti-tumor drugs while they induce apoptosis [28,29]. Melatonin was first discovered as a regulator of circadian rhythms, a characteristic that may contribute to its antitumoral effects [30][31][32][33]. There are also several publications reporting the proapoptotic effect of melatonin in cancer cell lines [34].…”

Circadian Dysfunction in a Rotenone-Induced Parkinsonian Rodent Model

“…Actograms, mean waveforms, cosinor, and Sokolove-Bushell periodograms were obtained. Furthermore, a nonparametric analysis of the recordings was performed for a duration of 7 d post treatment, as previously described Otalora et al, 2008). The relative amplitude (RA) of the rhythm represents the ratio between the most active 10-h span and the least active 5-h span.…”

“…Body temperature (BT) was continuously monitored at 60-min intervals throughout the experiment in a subset of animals (8 animals treated with rotenone and 6 control animals), using a miniature data logger (ThermoChron, Data loggers iButton; Maxim Integrated Products, Sunnyvale, CA, USA), as previously described Otalora et al, 2008). Sterilized data loggers were implanted intraperitoneally (i.p.)…”

The chronobiology, etiology and pathophysiology of obesity

“…54,61 Both human epidemiological and experimental studies of animals have documented that a potential negative consequence of CD is cancer initiation and development. 62 …”