Chronopharmacology of Melatonin in Mice to Maximize the Antitumor Effect and Minimize the Rhythm Disturbance Effect

Akagı, Takanori; Ushinohama, Kazami; Ikesue, Shoko; Yukawa, Eiji; Higuchi, Shun; Hamase, Kenji; Zaitsu, Kiyoshi; Ohdo, Shigehiro

doi:10.1124/jpet.103.055657

Cited by 14 publications

(12 citation statements)

References 33 publications

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“…Thus, the connection between aging, sirtuins, clock genes, and melatonin is beginning to be unraveled. Further studies are urgently needed to fully ascertain the importance of the restoration of physiological rhythms in cancer management, and also for assessing the proper scheduling of melatonin administration [146]. iv) Despite the well-known antioxidant properties of melatonin and its derivatives in normal tissues during many metabolic/hypoxic situations [147,148], the indole induces a transient rise in ROS production in several cancer cell lines [149,150].…”

Section: Expert Opinionmentioning

confidence: 99%

Molecular mechanisms of the pro-apoptotic actions of melatonin in cancer: a review

Bizzarri

Proietti

Cucina

et al. 2013

Expert Opinion on Therapeutic Targets

176

145

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Melatonin involvement in apoptotic processes is a new and relevant field of investigation. Even in tumor models unresponsive to melatonin alone, this hormone can significantly amplify the cytostatic and the cytotoxic effects triggered by other compounds or conventional drugs. We are far from having a satisfactory understanding about how and when melatonin exerts its beneficial effects. Melatonin in the nanomolar range activates the intrinsic and/or the extrinsic apoptotic pathway in cancer cells, namely through an increase in the p53/MDM2p ratio and downregulation of Sirt1. This finding is of great relevance since there is intense research ongoing to identify nontoxic feasible inhibitors of MDM2 and Sirt1. Melatonin should be evaluated for the management of those cancers where both of these are overexpressed and functionally strategic.

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Section: Expert Opinionmentioning

confidence: 99%

Molecular mechanisms of the pro-apoptotic actions of melatonin in cancer: a review

Bizzarri

Proietti

Cucina

et al. 2013

Expert Opinion on Therapeutic Targets

176

145

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“…(6,8,9) A preliminary study demonstrated that pretreatment of rats bearing hepatomas, for two weeks prior to a single dose of radiation administered just prior to lights off, with a non-tumor inhibiting dose of melatonin also given just before lights off, had a marked radiosensitizing effect. Pretreatment of tumor-bearing rats with AM doses of melatonin were ineffective.…”

Section: Introductionmentioning

confidence: 99%

Randomized Phase II Trial of High-Dose Melatonin and Radiation Therapy for RPA Class 2 Patients With Brain Metastases (RTOG 0119)

Berk¹,

Berkey²,

Rich³

et al. 2007

International Journal of Radiation Oncology*Biology*Physics

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Backround-RTOG 0119 was a Phase II randomized trial for RTOG RPA Class 2 patients with brain metastases to determine if high-dose melatonin improves survival over historical controls, and to determine if the time of day melatonin was given affects its toxicity or efficacy.Methods-RTOG RPA class 2 patients with brain metastases were randomized to 20 mg of melatonin given either in the morning (8-9 am) or evening (8-9 pm). All patients received radiation therapy (30 Gy in 10 fractions) in the afternoon. Melatonin was continued until neurological deterioration or death. The primary endpoint was overall survival time. Neurological deterioration as reflected by the Mini-Mental Status Exam was also measured.Results-Neither of the randomized groups had survival distributions that differed significantly from the historic control of patients treated with whole brain radiotherapy The median survivals of Corresponding Author: Lawrence Berk, MD, PhD, Radiation Oncology, Moffitt Cancer Center at Tampa General Hospital, 2 Columbia Dr., Tampa, FL 39606, E-mail: Berklb@moffitt.usf.edu. No conflicts of interest All patients gave IRB approved informed consent prior to enrolling on this trial.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access IntroductionMelatonin, an indoleamine molecule (N-acetyl, 5-methoxytryptamine) plays an important role in a number of processes including circadian rhythm regulation, sleep disorders, seasonal reproduction, retinal physiology, immune function, intermediary metabolism (1,2) and carcinogenesis. (3) It is also a highly efficient and potent free radical scavenger/antioxidant molecule and physiological blood levels of correlate with the total antioxidant capacity of the serum. (4) Oral ingestion of microgram amounts of melatonin results in near physiological nocturnal blood levels of melatonin. (5,6) The oral bioavailability of milligram doses of oral melatonin from nutritional supplements is about 15% (7) and results in supra-physiological melatonin levels.Numerous studies have demonstrated that physiological and pharmacological blood concentrations of melatonin inhibit tumorigenesis in a variety of in vivo and in vitro experimental models of neoplasia. (6,8,9) A preliminary study demonstrated that pretreatment of rats bearing hepatomas, for two weeks prior to a single dose of radiation administered just prior to lights off, with a non-tumor inhibiting dose of melatonin also given just before lights off, had a marked radiosensitizing effect. Pretreatment of tumor-bearing rats with AM doses of melatonin were ineffective. (10) The gre...

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“…Melatonin and its analogs have been documented to radioprotect normal tissues in a number of animal models while, at the same time, exerting direct antitumor effects [61][62][63][64][65][66][67]. Such results have led to the testing of melatonin as a radiation sensitizer for tumor cells and as a radioprotector for normal cells in a Phase II Radiation Therapy Oncology Group trial [68].…”

Section: • • Naturally Occurring Antioxidantsmentioning

confidence: 98%

Radioprotective Agents for Radiation Therapy: Future Trends

2014

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Only two radioprotective compounds, amifostine and palifermin, currently have the US FDA approval for use in radiation therapy. However, several agents have been reported that show therapeutic promise. Many of these agents are free radical scavengers/antioxidants. Superoxide dismutase and superoxide dismutase mimetics, nitroxides and dietary antioxidants are all being investigated. Recently, alternative strategies of drug development have been evolving, which focus on targeting the series of cellular insult recognition/repair responses initiated following radiation. These agents, which include cytokines/growth factors, angiotensin-converting enzyme inhibitors and apoptotic modulators, show promise of having significant impact on the mitigation of radiation injury. Herein, we review current literature on the development of radioprotectors with emphasis on compounds with proven or potential usefulness in radiation therapy.

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Chronopharmacology of Melatonin in Mice to Maximize the Antitumor Effect and Minimize the Rhythm Disturbance Effect

Cited by 14 publications

References 33 publications

Molecular mechanisms of the pro-apoptotic actions of melatonin in cancer: a review

Molecular mechanisms of the pro-apoptotic actions of melatonin in cancer: a review

Randomized Phase II Trial of High-Dose Melatonin and Radiation Therapy for RPA Class 2 Patients With Brain Metastases (RTOG 0119)

Radioprotective Agents for Radiation Therapy: Future Trends

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