Synergistic Cytotoxicity of Melatonin and New-generation Anticancer Drugs Against Leukemia Lymphocytes but not Normal Lymphocytes

Zhelev, Zhivko; Ivanova, Donika; Bakalova, Rumiana; Aoki, Ichio; Higashi, Tatsuya

doi:10.21873/anticanres.11300

Cited by 40 publications

(45 citation statements)

References 59 publications

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“…Melatonin in combination with doxorubicin led to reduction in ROS and protein‐carbonyl products levels and inhibition of apoptosis. These results were similar to the effects of melatonin plus everolimus and the combination of melatonin and barasertib . In contrast, a recent study observed that melatonin did not change the cytotoxicity of anticancer drugs including cyarabine, daunorubicin and etoposide in different myeloid leukemia cell types .…”

Section: Melatonin and Leukemiasupporting

confidence: 79%

“…Several experimental studies have reported that melatonin has positive and protective effects on different physiological reactions and in normal bone marrow cells suggested to be effective in leukemia therapy …”

Section: Introductionmentioning

confidence: 99%

“…27 Several experimental studies have reported that melatonin has positive and protective effects on different physiological reactions and in normal bone marrow cells suggested to be effective in leukemia therapy. 28,29 Current information about antitumor activity of melatonin against leukemia requires to be coordinated and merged to efficaciously evaluate the useful features of melatonin in leukemia treatment. Thus, the aim of our paper was to depict and summarize the main molecular targets of melatonin in leukemia models.…”

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confidence: 99%

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Melatonin: A promising agent targeting leukemia

Shafabakhsh

Mirzaei

Asemi

2019

J of Cellular Biochemistry

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Leukemia or cancer of blood is a well‐known cancer, which affects a range of people from newborns to the very old. It is a public health problem throughout the world. By way of treatment, due to the lack of specific anticancer therapies, common treatments of leukemia lead to severe side effects. Nonspecific anticancer drugs result in inhibition of normal cell growth and thereby their necrosis. Moreover, drug resistance is an additional problem, which stands in the way of leukemia treatment. Thus, finding new treatments for leukemia is essential. Melatonin, as a natural product, has been shown to be effective in a wide variety of diseases such as coronary heart disease, schizophrenia, chronic pain, and Alzheimer's disease. In addition, melatonin levels have been observed to be altered in different cancers, such as breast cancer, colorectal cancer endometrial cancer, and hematopoetical cancers. Anticancer features of melatonin such as pro‐oxidation, apoptosis induction, antiangiogenesis property and metastasis and invasion inhibition suggest that this natural compound can be used as a potential agent in novel therapeutic strategies for cancers. Also, it has been reported that melatonin has positive and protective effects on different physiological reactions and in normal bone marrow cells suggesting effectiveness in leukemia therapy. Thus, the aim of our paper was to depict and summarize the main molecular targets of melatonin on leukemia models.

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Section: Melatonin and Leukemiasupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Melatonin: A promising agent targeting leukemia

Shafabakhsh

Mirzaei

Asemi

2019

J of Cellular Biochemistry

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“…Melatonin has also been shown to exert antiproliferative and cytotoxic effects on human cancers, including colorectal cancer [7], neuroblastoma [8], hepatocarcinoma [9], lung cancer [10-12], breast cancer [13], prostate cancer [14, 15], and leukaemia [16, 17]. In a gastric cancer cell line it was already shown that proapoptotic effect of melatonin could be due to activation of a Caspase-dependent pathway and inhibition of the nuclear translocation of NF-κB p65, two processes that are regulated by p38 and c-Jun N-terminal kinase (JNK) [18].…”

Section: Introductionmentioning

confidence: 99%

Melatonin-Induced Changes in Cytosolic Calcium Might be Responsible for Apoptosis Induction in Tumour Cells

Chovancova

Hudecová

Lencesova

et al. 2017

Cell Physiol Biochem

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Background/Aims: Melatonin is a hormone transferring information about duration of darkness to the organism and is known to modulate several signaling pathways in the cells, e.g. generation of endoplasmic reticulum stress, oxidative status of the cells, etc. Melatonin has been shown to exert antiproliferative and cytotoxic effects on various human cancers. We proposed that this hormone can differently affect tumour cells and healthy cells. Methods: We compared the effect of 24 h melatonin treatment on calcium transport (by fluorescent probes FLUO-3AM and Rhod-5N), ER stress (determined as changes in the expression of CHOP, XBP1 and fluorescently, using Thioflavin T), ROS formation (by CellROX® Green/Orange Reagent) and apoptosis induction (by Annexin-V-FLUOS/propidiumiodide) in two tumour cell lines – ovarian cancer cell line A2780 and stable cell line DLD1 derived from colorectal carcinoma, with non-tumour endothelial cell line EA.hy926. Results: Melatonin increased apoptosis in both tumour cell lines more than twice, while in EA.hy926 cells the apoptosis was increased only by 30%. As determined by silencing with appropriate siRNAs, both, type 1 sodium/calcium exchanger and type 1 IP₃ receptor are involved in the apoptosis induction. Antioxidant properties of melatonin were significantly increased in EA.hy926 cells, while in tumour cell lines this effect was much weaker. Conclusion: Taken together, melatonin has different antioxidative effects on tumour cells compared to non-tumour ones; it also differs in the ability to induce apoptosis through the type 1 sodium/calcium exchanger, and type 1 IP₃ receptor. Different targeting of calcium transport systems in tumour and normal, non-tumour cells is suggested as a key mechanism how melatonin can exert its anticancer effects. Therefore, it might have a potential as a novel therapeutic implication in cancer treatment.

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“…However, there are a handful of published reports that indicate melatonin may have selective toxicity to cancer cells. Synergistic cytotoxicity of melatonin and anticancer drugs toward leukemia lymphocytes but not normal lymphocytes has been described [61]. Furthermore, viability of malignant cells but not their normal counterparts is reduced by melatonin [62].…”

Section: Evidence That Melatonin Slows Rate Of Cancer Progression mentioning

confidence: 99%

Mechanisms Underlying Tumor Suppressive Properties of Melatonin

Bondy

Campbell

2018

IJMS

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There is considerable evidence that melatonin may be of use in the prevention and treatment of cancer. This manuscript will review some of the human, animal and cellular studies that provide evidence that melatonin has oncostatic properties. Confirmation that melatonin mitigates pathogenesis of cancer will be described from both direct study of its effects on carcinogenesis, and from indirect findings implicating disruption of the circadian cycle. A distinction is made between the role of melatonin in preventing the initiation of the tumorigenic pathway and the ability of melatonin to retard the progression of cancer. Melatonin appears to slow down the rate of advancement of established tumors and there is evidence that it constitutes a valuable complement to standard pharmacological and radiation treatment modalities. There are instances of the beneficial outcomes in cancer treatment which utilize a range of hormones and vitamins, melatonin being among the constituents of the mix. While these complex blends are empirically promising, they are only briefly mentioned here in view of the confounding influence of a multiplicity of agents studied simultaneously. The last section of this review examines the molecular mechanisms that potentially underlie the oncostatic effects of melatonin. Alterations in gene expression following activation of various transcription factors, are likely to be an important mediating event. These changes in gene activity not only relate to cancer but also to the aging process which underlies the onset of most tumors. In addition, epigenetic events such as modulation of histone acetylation and DNA methylation patterns throughout the lifespan of organisms need to be considered. The antioxidant and immunoregulatory roles of melatonin may also contribute to its cancer modulatory properties. Naturally, these mechanisms overlap and interact extensively. Nevertheless, in the interest of clarity and ease of reading, each is discussed as a separate topic section. The report ends with some general conclusions concerning the clinical value of melatonin which has been rather overlooked and understudied.

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Synergistic Cytotoxicity of Melatonin and New-generation Anticancer Drugs Against Leukemia Lymphocytes but not Normal Lymphocytes

Cited by 40 publications

References 59 publications

Melatonin: A promising agent targeting leukemia

Melatonin: A promising agent targeting leukemia

Melatonin-Induced Changes in Cytosolic Calcium Might be Responsible for Apoptosis Induction in Tumour Cells

Mechanisms Underlying Tumor Suppressive Properties of Melatonin

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