Antitumor Effects Of Melatonin Research Articles

The role and therapeutical potential of melatonin in oncology practice

This review describes the available works on four main trends of prospective application and study of melatonin in oncology: the main properties and mechanisms of the antitumor effect of melatonin, melatonin as a direct antitumor agent, melatonin as a drug for the accompanying therapy of psychoemotional disorders and sleep disorders in cancer patients, and melatonin as a drug for the accompanying therapy of chronic pain syndrome in oncology. Currently, researchers focus on fundamental and clinical relationships between circadian rhythms and carcinogenesis, and one of the key problems is the potential of melatonin as an agent capable of interfering with the molecular processes of formation and maintenance of the viability of malignant tumors. An equally important problem is the potential of melatonin in terms of using its physiological properties for the prevention and accompanying therapy of undesirable effects of the main treatment in oncological practice, which is emphasized in this review. The purpose of this review is an unbiased study of the prospects for the multidirectional use of melatonin both as a direct antitumor agent and as a component of complex therapy of concomitant adverse events associated with tumor and the treatment. Based on a detailed analysis of original scientific articles and scientific reviews in the PubMed search system, as well as peer-reviewed Russian journals, authors have made an attempt to characterize the current state of melatonin in oncology based on principles of evidence-based medicine. Authors also suggests and justify key prospects for use of melatonin in oncology practice and the range of studies necessary to clarify its properties and place in the combined therapy of malignant neoplasms.Received 9 July 2021. Revised 18 August 2021. Accepted 19 August 2021.Funding: The study did not have sponsorship.Conflict of interest: Authors declare no conflict of interest.Contribution of the authors Conception and study design: I.I. Eremenko, V.E. Ponomarev Drafting the article: I.I. Eremenko, V.E. Ponomarev, S.B. Polikarpova, E.A. Bogush, V.Yu. Kirsanov, B.A. Zisman, M.M. Davydov Critical revision of the article: I.I. Eremenko, V.E. Ponomarev Final approval of the version to be published: I.I. Eremenko, V.E. Ponomarev, S.B. Polikarpova, E.A. Bogush, V.Yu. Kirsanov, B.A. Zisman, M.M. Davydov

Melatonin Inhibits the Malignant Progression of Glioblastoma via Regulating miR-16-5p/PIM1.

Melatonin (MT) is a pineal hormone with antineoplastic potential. This study aims to explore the therapeutic potential and mechanism of MT on glioblastoma (GBM). A human GBM cell line, LN229, was used to evaluate the function of MT. Cell viability, apoptosis, and migration were detected by CCK-8, flow cytometry, and transwell assays, respectively. The mRNA and protein expressions of specific genes were measured by qRT-PCR and western blot, respectively. The regulatory relationship between miR-16-5p and PIM1 was validated by dual luciferase reporter gene assay. A mouse xenograft model was established to prove the anti-tumor effect and related mechanisms of MT in vivo. MT inhibited the viability and migration and promoted the apoptosis of LN229 cells in a dose-dependent manner. MiR-16-5p was dose-dependently up-regulated by MT in LN229 cells, negatively regulating its target PIM1. MiR-16-5p inhibitor eliminated the anti-tumor effect of MT in LN229 cells, while si-PIM1 reversed the effect of miR-16-5p inhibitor in MT-treated cells. MT inhibited the tumor growth in vivo and MT-induced PIM1 down-regulation was reversed by miR- 16-5p inhibition in tumor tissues. MT inhibits the malignant progression of GBM via regulating miR-16-5p-mediated PIM1.

Inhibitory effect of melatonin on hypoxia-induced vasculogenic mimicry via suppressing epithelial-mesenchymal transition (EMT) in breast cancer stem cells.

Vasculogenic mimicry (VM) play an important role in breast cancer metastasis and anti- angiogenic drugs resistance. Hypoxia, the epithelial-mesenchymal transition (EMT), and cancer stem cells (CSCs) are known as essential factors for VM formation. Also, melatonin is an amino acid-derived hormone with many anti-tumor effects. Despite the antitumor effects of melatonin, its effect on VM formation in breast cancer has not been considered yet, so we investigated the effect of melatonin on VM formation through EMT process under hypoxia conditions in breast CSCs. The CSCs percentage and VM formation were determined in MCF-7 and MDA-MB-231, respectively. Also, analysis of HIF-1α expression under hypoxia in MDA-MB-231 and MCF-7 cell lines was performed using Western blot. The effect of melatonin on the VM formation, invasion, and migration was also investigated. Moreover, the effect of melatonin on the expression EMT markers was evaluated. CD44+ CD24-phenotype as CSCs marker in MDA-MB-231 cell line, was 80.8%, while it was 11.1% in MCF-7 cell line. HIF-1α expression was up-regulated in the VM-positive breast cancer cell line MDA-MB-231, and consequently, affected the expression of the EMT markers E-cadherin, vimentin, snail, and MMP9. Melatonin had significant effect on EMT and formations of VM in breast CSCs. Melatonin could prevent the formation of VM by affecting the important molecules involved in the formation of VM structures and the EMT. Moreover, our data clearly showed that, melatonin represents molecule with significant anti-cancer activities that may potentially optimize the management of breast cancer through the overcoming drug resistance in anti-angiogenic drugs.

Melatonin enhances sorafenib-induced cytotoxicity in FLT3-ITD acute myeloid leukemia cells by redox modification.

Acute myeloid leukemia (AML) with an internal tandem duplication in Fms-related tyrosine kinase 3 (FLT3-ITD) is identified as a subgroup with poor outcome and intrinsic resistance to chemotherapy and therefore urgent need for development of novel therapeutic strategies.Methods: The antitumor effects of melatonin alone or combined with sorafenib were evaluated via flow cytometry and immunoblotting assays in FLT-ITD AML cells. Also, the ex vivo and in vivo models were used to test the synergistic effects of melatonin and sorafenib against leukemia with FLT3/ITD mutation.Results: Our study shows for the first time that melatonin inhibits proliferation and induces apoptosis in FLT3/ITD-positive leukemia cells. Mechanistically, melatonin preferentially causes overproduction of reactive oxygen species (ROS) and ultimately massive cell death in FLT3-ITD AML cells. Moreover, melatonin significantly enhances the cytotoxicity induced by the FLT3 tyrosine kinase inhibitor sorafenib in AML cells with FLT3/ITD through redox modification. Importantly, combination of melatonin and sorafenib exhibited highly synergistic therapeutic activity in MV4-11 xenografts and a murine model bearing FLT3/ITD leukemia.Conclusion: This study indicates that melatonin, alone or in combination with sorafenib, has potential to improve the therapeutic outcome of AML patients with FLT3-ITD mutation that merits further investigation.

Mitochondrial cytochrome P450 (CYP) 1B1 is responsible for melatonin-induced apoptosis in neural cancer cells.

Melatonin is an endogenous indoleamine with a wide range of biological functions in the various organisms from bacteria to mammals. Evidence indicates that melatonin facilitates apoptosis in cancer cells and enhances the antitumor activity of chemotherapy in animals and clinical studies. However, the melatonin metabolism and the key metabolic targets in cancer cells still remain unknown. In this study, U118 and SH-SY5Y tumor cell lines were used to investigate the metabolic pathways of melatonin in cancer cells. Interestingly, the inhibitory effect of melatonin on proliferation in SH-SY5Y cells is more potent than that in U118 cells. In contrast, this inhibitory effect on the normal cells is absent. The antitumor effects of melatonin are positively associated with its metabolite N-acetylserotonin (NAS). Unexpectedly, CYP1B1 is, for first time, identified to localize in the mitochondria of tumor cells, and it metabolizes melatonin to form NAS in situ, which subsequently triggers mitochondria-dependent apoptosis in cancer cells. In normal cells, NAS does not induce apoptosis. A remarkable individual variation on CYP1B1 expression was also detected in human tumor tissue. These findings provide the novel mechanisms regarding the antitumor effects of melatonin in the level of mitochondria. Thus, we hypothesize that CYP1B1 overexpression in mitochondria would significantly enhance the antitumor effects of melatonin. Mitochondrial CYP1B1 can potentially serve as a specific target to modify the therapeutic and biological effects of melatonin on cancer patients.

Abstract 3446: Melatonin suppresses hepatocellular carcinoma progression via lncRNA-CPS1-IT-mediated HIF-1α inactivation

Abstract Background: Melatonin, the main pineal hormone that relays light/dark cycle information to the circadian system, was recently reported to have intrinsic antitumor activity in various cancers. However, the detailed regulatory mechanisms associated with antitumor activity of melatonin are not well understood yet. Moreover, limited studies have addressed the role of melatonin in hepatocellular carcinoma (HCC), the major life-threatening malignancy for both sexes in Taiwan. Hence, in this study, we investigated the antitumor activity of melatonin on HCC and explored its regulatory mechanism. Methods: Human hepatoma cell lines HepG2 and Huh7 were treated with melatonin followed by functional assays to dissect antitumor effect of melatonin in HCC. The whole transcriptome sequence analysis was performed to explore the long non-coding RNAs (lncRNAs) involved in the anti-HCC activity of melatonin. Further, quantitative RT-PCR, western blot, immunohistochemistry assays, and in vivo animal model experiments were performed to elucidate the regulatory mechanism of lncRNAs in melatonin-mediated HCC suppression. Results: Melatonin significantly inhibited cell proliferation, migration, and invasion capacity of HCC cell lines, while the expression of transcription factor FOXA2 was significantly induced in cells treated with melatonin. The increase in expression of FOXA2 resulted in upregulation of lncRNA-CPS1-IT1 expression, which in turn reduced binding and activation of Hsp90 with HIF-1α. The inactivation of HIF-1α resulted in the suppression of epithelial-mesenchymal transition (EMT) progression and HCC metastasis. Furthermore, the results of the in vivo animal model experiments also validated the tumor-suppressor role of melatonin via a reduction in tumor growth. Conclusions: Taken together, our findings suggested that melatonin inhibited HCC progression by modulating lncRNA-CPS1-IT1-mediated EMT suppression and further supported melatonin as a promising therapeutic agent for the treatment of HCC. Note: This abstract was not presented at the meeting. Citation Format: Tong Hong Wang, Chi Hao Wu, Chau Ting Yeh, Kung Hao Liang, Chuen Hsueh, Chi Yuan Chen. Melatonin suppresses hepatocellular carcinoma progression via lncRNA-CPS1-IT-mediated HIF-1α inactivation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3446. doi:10.1158/1538-7445.AM2017-3446

Glioma, Melatonin, and Radiotherapy

To the Editor:Accumulative evidence indicates antitumor effects of melatonin in a variety of malignancies (1, 2). Accordingly, Martin et al. have recently reported cell growth inhibition of glioma by melatonin (3). This study is of peculiar interest because melatonin is produced in the brain by the pineal gland. This location of the pineal gland, near the center of the brain, suggests that in addition to hypothalamic-pituitary dysfunctions (4), a melatonin deficiency could also occur in some patients following brain radiotherapy (5). Although the consequences of melatonin deficiency on glioma growth remain to be investigated, the report of Martin et al. have important implications for the development of a possible circadian-based cancer therapy of glioma. Moreover, it highlights the importance of determining the pineal status of patients following brain radiotherapy, by measuring, for example, the melatonin metabolite 6-sulphatoxymelatonin in the first morning urine (6). In addition to its relevance in the follow-up of patients, this dosage could help to further elucidate the link between melatonin and glioma growth.

Chemopreventive Effects of Melatonin on Diethylnitrosamine and Phenobarbital-Induced Hepatocarcinogenesis in Male F344 Rats

The antitumor effects of melatonin on diethylnitrosamine (DEN)-initiated and/or phenobarbital (PB)-promoted hepatocarcinogenesis were investigated in male F344 rats. Five-week-old male F344 rats were divided into eight groups. Rats in groups 1-5 were given DEN (100 mg/kg body weight, i.p.) once a week for 3 wk, whereas those in groups 6-8 received vehicle treatment. Groups 1-3 and 7 were given 500 ppm PB in drinking water for 20 wk after DEN or vehicle treatment. Group 2 was given 400 ppm melatonin-containing diet during the initiation phase. Groups 3 and 5 were fed melatonin-containing diet for 20 wk, starting 1 wk after the last dosing of DEN. Group 6 was given melatonin-containing diet alone throughout the experiment (24 wk). Group 8 was treated with vehicle alone. Liver neoplasms were recognized only in DEN-treated groups. The incidences and multiplicities of hepatocellular adenoma and hepatocellular carcinoma (HCC) in group 3 were significantly smaller when compared with group 1 (P < 0.001 or P < 0.002). The average and unit areas of glutathione S-transferase placental form (GST-P)-positive foci of groups 2 and 3 were significantly smaller than those of group 1 (P < 0.001 or P < 0.01). The density and average area of these preneoplastic lesions of group 5 were also smaller than those of group 4 (P < 0.001 or P < 0.005). In addition, the ornithine decarboxylase activity in nonneoplastic liver tissue was reduced by melatonin treatment in both the initiation and postinitiation phases. These results suggest that melatonin has an antitumor-promoting ability in DEN-initiated and PB-promoted hepatocarcinogenesis in rats.

Chronopharmacology of melatonin in mice to maximize the antitumor effect and minimize the rhythm disturbance effect.

The influence of dosing time on the antitumor effect and the rhythm disturbance effect of melatonin (MLT) was investigated in ICR male mice under a light/dark (12:12) cycle. In tumor-bearing mice, the antitumor effect of MLT (1 mg/kg intraperitoneal) was most effective in the dark phase; and the rhythm disturbance effect of MLT on the locomotor activity was more serious in the light phase than in the dark phase. The antitumor effect and the rhythm disturbance effect of MLT increased when the specific binding of MLT receptor in target tissues, tumor or suprachiasmatic nucleus, increased and they decreased when the level decreased. Furthermore, because luzindole, an MT1 and MT2 blocker, caused the antitumor effect or rhythm disturbance effect of MLT to decrease, it is suggested that the time-dependent change of the pharmacological effects of MLT were influenced by that of MLT receptor(s) function. On the other hand, there was no significant dosing time-dependent change of MLT concentration in tumor or brain after injection. Thus, the pharmacokinetic factor does not seem to contribute to the dosing time-dependent effect of MLT. These results suggest that by choosing the most suitable dosing time for MLT, the efficacy of the drug can be increased, and the toxicity of the drug can be decreased in certain experimental and clinical situations.