key: cord-0016422-6riphakl
authors: Mehrzadi, Saeed; Pourhanifeh, Mohammad Hossein; Mirzaei, Alireza; Moradian, Farid; Hosseinzadeh, Azam
title: An updated review of mechanistic potentials of melatonin against cancer: pivotal roles in angiogenesis, apoptosis, autophagy, endoplasmic reticulum stress and oxidative stress
date: 2021-03-31
journal: Cancer Cell Int
DOI: 10.1186/s12935-021-01892-1
sha: 322f8e722ca21bbcd90c4395e539ec6babb2ee5f
doc_id: 16422
cord_uid: 6riphakl

Cancers are serious life-threatening diseases which annually are responsible for millions of deaths across the world. Despite many developments in therapeutic approaches for affected individuals, the rate of morbidity and mortality is high. The survival rate and life quality of cancer patients is still low. In addition, the poor prognosis of patients and side effects of the present treatments underscores that finding novel and effective complementary and alternative therapies is a critical issue. Melatonin is a powerful anticancer agent and its efficiency has been widely documented up to now. Melatonin applies its anticancer abilities through affecting various mechanisms including angiogenesis, apoptosis, autophagy, endoplasmic reticulum stress and oxidative stress. Regarding the implication of mentioned cellular processes in cancer pathogenesis, we aimed to further evaluate the anticancer effects of melatonin via these mechanisms.

As the second cause of mortality worldwide, new cases of cancer have recently been reported to increase by 2025 (approximately 19.3 million annually) [1] . Cancer growth control, complete eradication and preventing its incidence are main purposes for cancer-associated investigations. Chemotherapy, radiotherapy and surgery are the major conventional anticancer treatments. The restricted efficiency of these treatments as well as their dangerous side effects have forced researchers to find novel effective anticancer therapies based on herbal extracts and natural compounds as single or combined therapies [2] [3] [4] .

Melatonin, a multifunctional pleiotropic neurohormone secreted by the pineal gland and other organs including bone marrow, retina, and skin. It is an immune regulatory agent and powerful antioxidant with a capability of preventing cell death in oxidative stress situations. [5, 6] . Moreover, melatonin interrupts cell death mechanisms, inflammation, and redox activity probably resulting in cancer cells sensitization to chemotherapy and radiation [7] .

Cancer Cell International Furthermore, in addition to diverse therapeutic potentials for several diseases [8, 9] , melatonin has been shown to possess anticancer abilities against skin cancer [10] , glioma [11] , lung cancer [12] , gastrointestinal cancers [13] , gynecological cancers [14, 15] , and hematological cancers [16, 17] . Although mechanistic impacts of melatonin on various cancers have been widely demonstrated, in the present review we discuss anticancer effects of melatonin with focusing on molecular pathways including angiogenesis, apoptosis, autophagy, endoplasmic reticulum stress, and oxidative stress.

Monitoring of circadian rhythm is one of the several properties of melatonin, which also possesses oncostatic, vasoregulation, antioxidant, anti-inflammatory, and immunomodulatory abilities [18, 19] . It has been demonstrated that the normally enhanced melatonin levels at night help in the organization of homeostatic metabolic rhythms of targeted organs and systems [20] . Of note, disruption of circadian rhythm has been shown as one of the contributing factors in cancer progression and development [21] .

Melatonin, as an antioxidant agent, scavenges free radicals. Melatonin has protective effects on neurodegenerative disorders, epilepsy, and cancer through inhibiting oxidative stress in vitro and in vivo [22, 23] . Melatonin increases the activity and expression of enzymes, including catalase, superoxide dismutase and glutathione peroxidase, implicated in antioxidant abilities [24, 25] . Melatonin also has anti-inflammatory impacts and attenuates pathogenic inflammation through modulating different pathways, including reducing the secretion of tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-2) and interferon-gamma (IFN-γ), and enhancing the amounts of IL-4, IL-10 and IL-27. Melatonin alleviates pro-inflammatory cytokines secretion via suppressing nuclear factor kappa B (NF-κB) [26] [27] [28] . In addition, in neurodegenerative disorders, melatonin blocks cyclooxygenase-2 (COX-2) expression, a pro-inflammatory mediator [29] . Melatonin inhibits apoptosis through regulating Bax/Bcl2 and decreasing caspase-3 activity and expression, proposing that melatonin modulates apoptotic functions in the protection against malignancy and neurodegenerative disorders [30] [31] [32] .

Melatonin regulates multiple physiological and neural functions (Fig. 1) . Among of them, effects on blood lipid profile, glycemic control, gestation, reproduction, and fetal development, neural protection, immune system, and cardiovascular system have been widely documented [33, 34] . Melatonin prevents the growth and promotion of spontaneous and chemically mediated breast tumors [35, 36] . Moreover, at physiological concentrations, melatonin suppresses cell invasiveness and proliferation in breast cancer cells [37] .

In this section we describe the effect of melatonin on oxidative stress and endoplasmic reticulum stress, and various signaling pathways including angiogenesis, apoptosis, autophagy affected by melatonin in different cancer cells (Fig. 2) .

Angiogenesis is a crucial event implicated in the progression of tumor as well as its metastasis [38] . Hypoxia in the central areas of solid tumor is a leading cause of angiogenesis via activation of angiogenic mediators [38, 39] . Vascular endothelial growth factor (VEGF), the specific mitogen of endothelial cells and the most active pro-angiogenic agent, is a powerful angiogenesis enhancer which increases vascular permeability. Numerous data suggest that, in tumor development, anti-VEGF therapy has important roles in the suppression of tumor cell growth, leading to a considerable amelioration in progression-free survival [40] . Hypoxia-inducible factor-1 (HIF-1) is another key factor in angiogenesis, which modulates hypoxia-activated genes transcription and consists of HIF-1α and HIF-1β heterodimer. The α subunit of HIF-1 is stabilized under hypoxia and degraded under normoxic situations, however, HIF-1β is expressed constitutively [41] .

Melatonin has been shown to have regulatory role in angiogenesis process [42] . In other words, melatonin possesses various impacts on neovascularization under diverse pathological and physiological situations. In skin lesions, gastric ulcers, and some physiologic events, melatonin promotes angiogenesis, while in a hypoxic environment, in age-related ocular diseases, and in tumors melatonin suppresses neovascularization in tissues [43] .

Melatonin exerts its antitumor potentials via inhibiting HIF-1-induced angiogenesis [44] . Furthermore, melatonin inhibits the accumulation of HIF-1α through suppressing the formation of ROS and the sphingosine kinase 1 (SPHK1) pathway in prostate cancer cells under hypoxic conditions [45] . Melatonin plays an important role in the paracrine interaction between proximal endothelial cells and malignant epithelial cells by a downmodulatory effect on the expression of VEGF in breast tumor cells, which reduces VEGF levels around endothelial cells [46] .

Of note, anti-angiogenic potential of melatonin is a key factor resulting in the inhibition of proliferation of cancer cells, as demonstrated in various investigations. For instance, melatonin attenuates proliferation of prostate cancer cells triggered by epidermal growth factor [47] . Melatonin also hampers vasculogenic mimicry of oral cancer cells via inhibition of ROS-activated Akt and ERKs signaling pathway implicating the HIF-α pathway [48] . Melatonin up-regulates TGF-β1 expression in tumor tissues during the inhibition of gastric cancer tumor growth process [49] . Furthermore, apoptotic and anti-proliferative effects of melatonin on breast cancer cells are mediated by the simultaneous activation of the Apaf-1/caspase-dependent apoptotic pathway and the inhibition of PI3K/Akt, p300/NF-κB, and COX-2/PGE2 signaling pathways [32] .

Endothelin-1 is a peptide acting as a survival factor in colon cancer, promoting angiogenesis and mediating cell proliferation. Melatonin suppresses endothelin-1 mRNA expression. Also, melatonin blocks the activity of endothelin-1 promoter modulated by NF-κβ and FoxO1 [50] . Melatonin represses ROCK-1, VEGF and HIF-1α genes expressions in oral cancer [51] . Melatonin alters the expression of inflammatory and angiogenic proteins in both co-culture and monoculture of cancer cells and cancer-associated fibroblasts [52] . Melatonin suppresses tumor angiogenesis and the growth of gastric cancer cells in tumor-bearing nude mice. Moreover, melatonin decreases the expression of VEGF and HIF-1α at translational and transcriptional levels within gastric cancer cells during tumorigenesis [53] . Reduced serum levels of VEGF have been reported in cancer subjects treated with [54] . Vimalraj et al. [55] showed that melatonin upregulates miR-424-5p expression in osteosarcoma cells suppressing VEGFA. Furthermore, it inhibits tumor angiogenesis, regulating surrounding endothelial cells migration and proliferation, and angiogenic growth factors and the morphology of blood vessels E (Table 1) .

In normal cellular condition, there is a balance between the production of oxidants, so called reactive oxygen species (ROS), and their neutralizing compounds, named antioxidants. The state of excess ROS, in which the oxidant content of the cells dominates the neutralizing capacity of antioxidants, is defined as oxidative stress [56, 57] . Sustained oxidative stress increases the risk of cancer development either through inducing mutagenesis or by promoting the expression of proto-oncogenes such as cyclin D1. It also plays a signaling role in the [54] activation of several genes involved in the cancer progression including the mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK) and JUN N-terminal kinase (JNK) [58, 59] . Melatonin role as a natural ally against oxidative stress has been revealed in many in vitro and in vivo studies. Detoxification of oxidants by melatonin is triggered by several direct or indirect mechanisms. In direct scenario, melatonin neutralizes the oxidants by its nonreceptor-mediated free radical scavenging capacity. As indirect scenario, melatonin reduces the oxidative content through several mechanisms such as activating anti-oxidative enzymes and suppressing pro-oxidative enzymes. It also stabilizes the mitochondrial inner membrane, thereby maintaining mitochondrial integrity leading to a reduced electron leakage and ROS generation [60, 61] .

The inducing role of oxidative stress in cancer progression and preventive role of melatonin in the production and function of oxidants indicated a possible oncostatic property for melatonin [62] . Subsequently, it was revealed that melatonin reduces the oxidative damage to cellular components under conditions where toxic oxygen derivatives are acknowledged to be released [63, 64] . Moreover, in vitro studies demonstrated that melatonin treatment reduces the amount of oxidative contents in a variety of cancer cells, which was further supported by in vivo studies ( Table 2) .

Endoplasmic reticulum (ER) is an entry site for secretory proteins and most integral membrane proteins for proper folding and covalent modifications to assemble into a functional complex. In addition to the processing of proteins, ER is involved in various cellular functions including lipid synthesis, fatty acid turnover, detoxification, Ca 2+ homeostasis. The ER network extends into all cell compartments to sense intrinsic and extrinsic perturbations and integrate the stress signals for maintenance of cellular homeostasis to preserve proper cellular and organismal function [65, 66] . However, the ER function can be impacted and disturbed by a multitude of exogenous and endogenous factors, leading to the accumulation of mis/unfolded proteins in the ER. This causes the imbalance between the client proteins load in the lumen of ER and the folding capacity of this organelle leading to the failure of the ER to cope with unusual high protein folding load, which is termed 'ER stress' [67] . To restore protein homeostasis, an adaptive signal transduction pathway called the unfolded protein response (UPR) is activated to induce compensatory responses to stressors for recovering normal ER function [68] . Signaling proteins sensing UPR include inositol-requiring protein-1α (IRE1α), activating transcription factor 6α (ATF6α) and protein kinase RNA (PKR)-like ER kinase (PERK). In nonstressed cells, UPR stress sensors are maintained in an inactive state through direct binding to the ER chaperone proteins, Bip (78-kDa glucose regulated protein, GRP78). Upon ER stress, aggregation of misfolded proteins leads to the dissociation of UPR sensors from Bip, which causes activation of UPR signals [69] . Although activation of UPR signaling pathways is a cellular strategy to increase survival, this pathway will instead activate cell death signaling pathways when the intensity or duration of cellular stress increases. Therefore, certain anti-cancer patterns may activate ER stress/ UPR pathway to induce apoptosis in cancer cells [70] .

Melatonin induces mitochondria-mediated apoptosis in colorectal cancer cells through reducing the expression of PrP C and PINK1 resulting in the enhancement of superoxide production and induction of ER stress [71] . Melatonin also ameliorates ER-stress mediated insulin resistance. ER stress induces autophagy in pancreatic β cells, which this pathway plays an important role in insulin production and secretion. In the glucose analog 2-DG-treated rat insulinoma INS-1E cells, melatonin reduces insulin production via ER stress-induced autophagy [72] . Combination of melatonin with ER stress inducer tunicamycin increases the sensitivity of cancer cells to apoptosis through inhibiting the expression of COX-2 and increasing the Bax/Bcl-2 ratio and CHOP levels [73] . Selective inhibition of ATF-6 by melatonin results in the suppression of COX-2 production and enhancement of cancer cells to ER-stress induced apoptosis [74] .

Melatonin increases apoptosis through enhancing caspase-3, -8 and -9 activities, Bax/Bcl-2 ratio, PARP cleavage and cytochrome c, p53 and Fas-L proteins concentrations in hepatocellular carcinoma, which this effect is mediated by the elevation of ER stress characterized by up-regulation of ATF6, CHOP and Bip [75] . Furthermore, melatonin increases the sensitivity of hepatocellular carcinoma cells to sorafenib through targeting the PERK-ATF4-Beclin1 pathway [76] . The same results have been reported in gastric cancer; melatonin inhibits cell proliferation through inducing activation of the IRE/ JNK/Beclin1 signaling [77] .

Melatonin in combination with the ER stressor thapsigargin increases the expression level of nuclear mammalian RNA-binding protein (HuD) resulting in the reduction of intracellular biosynthesis of insulin. Suppression of AKT/PI3K pathway and induction of nuclear mTOR (Ser2481, Ser2448) expressions by melatonin sensitizes rat insulinoma INS-1E cells to insulin through increasing the expression of insulin receptor substrate [78] . In contrast with these reports, melatonin has been reported to inhibit tunicamycin-induced ER stress in human hepatocellular carcinoma cells and increase the response of these cells to cytotoxic effects of doxorubicin; this is accompanied by inhibition of the PI3K/AKT pathway, elevation of CHOP and reduction of Survivin [79] .

These evidences suggest that melatonin could improve the toxic effect of anti-cancer agents on cancer cells through regulating ER stress in cells (Table 3) . 

Autophagy is a complicated process maintaining intracellular homeostasis by eliminating degraded proteins and organelles during cellular stress. Autophagy is principally considered as a pro-survival process, but, excessive or inappropriate autophagy contributes to the cell death, a process known as autophagic cell death or type II programmed cell death [80] . Autophagy is a complicated process, which consists of five sequential steps, including: (a) initiation complex formation and double-membrane phagophore (nucleation) maturation; (b) membrane elongation and autophagosome formation sequestering cargo; (c) fusion with lysosome; (d) inner membrane disruption leading to degradation of cargo by hydrolases; and (e) macromolecular component utilization [81] . These steps of the autophagy pathway are regulated by more than 35 autophagy related genes (ATGs) and proteins most of which function in complexes. The initiation phase is regulated by Unc-51-like kinase1 (mammalian homologues of Atg1, ULK1)-Atg13-Atg101-FIP200 (mammalian homologues of Atg17) protein complex. Unc-51-like kinase1 phosphorylates and activates Beclin-1 (mammalian homologue of Atg6). Beclin-1 is a part of multiproteincomplex, class III PI3-kinase Vps34-p150 (mammalian homolog of Vps15)-Atg14-like protein (Atg14L)-Beclin-1, promoting nucleation [81] [82] [83] . The elongation phase is regulated by two ubiquitin-like conjugation systems, Atg12 and LC3 (mammalian homologue of Atg8). In the first conjugation system, Atg12 is activated by Atg7 (E1-like enzyme), transferred to Atg10 (E2-like enzyme) and conjugated to Atg5. The Atg12-Atg5 conjugates further couples with Atg16 (Atg16L in mammals) to form the E3-like complex. In the LC3 conjugation system, LC3 is cleaved by a cysteine protease, Atg4, forming LC3-I. Thereafter, LC3-I is activated by Atg7 (E1-like enzyme), transferred to Atg3 (E1-like enzyme) and conjugated to phosphatidylethanolamine (PE) to form LC3-II; this process is facilitated by the E3-like complex. This lipidated form of LC3, LC3-II, is recruited to the autophagosome membrane. Finally, the Atg9 dependent pathway promotes autophagosome membrane expansion [81] [82] [83] .

Cargo sequestration can be selective or non-selective; the selectivity is based on autophagy receptors such as P62/SQSTM1, NBR1, NDP52, NIX/BNIP3L, BNIP3 and FUNDC1 [82] . Fusion of autophagosome with lysosome is the next step. The inner vesicle is degraded by lysosomal hydrolases, including cathepsin B, D (a homolog of proteinase A), and L. The degradation products are released to the cytosol and used in different anabolic pathways [84] . ER stress-induced activation of UPR pathways promotes induction of autophagy [85] . Activated PERK/ATF4 pathway up-regulates the expression of ATG genes including ATG5, ATG7, and ATG10 [86] . The conversion of LC3-I conversion to LC3-II is also induced by PERK pathway [87] . Activation of IRE1α pathway induces the expression of Beclin1 and the phosphorylation of Bcl-2 by JNK, which subsequently results in the Bcl-2-Beclin 1 dissociation [88] [89] [90] . The release of Ca 2+ from ER to cytosol triggers autophagy pathway through activating several mechanisms including (I) inhibition of mTOR by Ca 2+ /calmodulin dependent kinase kinase-β-mediated activation of AMP-activated protein kinase (AMPK) [91] , and (II) dissociation of Bcl-2-Beclin 1 by inducing death-associated protein kinase (DAPK) 3-mediated Beclin 1 phosphorylation [92] .

Melatonin has a modulatory effect on autophagy in various cell types and different conditions. Melatonin indirectly modulates autophagy through affecting oxidative stress, ER stress and inflammation [69] . Melatonin enhances the effectiveness of cisplatin and radiotherapy in head and neck squamous cell carcinoma, which this effect is mediated by the excessive activation of mitochondria leading to the over-production of ROS and subsequent induction of autophagy and apoptosis [93] . Melatonin also increases cytotoxic effects of rapamycin in cancer cells. Combination of rapamycin and melatonin suppresses AKT/mTOR pathway activation, which this effect leads to the enhancement of mitochondrial function and ROS production resulting in the induction of apoptosis and mitophagy [94] . Melatonin induces autophagy in clear cell renal cell carcinoma through activating transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1A (PGC1A) and uncoupling protein 1 (UCP1); this is associated with the elimination of lipid deposits without generating ATP, which subsequently leads to the tumor size reduction [95] .

Melatonin reduces the viability liver cancer cells through transient induction autophagy by up-regulating JNK phosphorylation. However, ATG5 silencing sensitizes cancer cells to melatonin-induced apoptosis. This suggests that modulation of autophagy by melatonin has dual effect on cell death [96] . Similarly, disruption of autophagy sensitizes glioblastoma cells and tongue squamous cell carcinoma to melatonin-induced apoptosis [97] . Melatonin-induced autophagy is suggested to be mediated by activation of melatonin membrane receptor in tongue squamous cell carcinoma and suppression of melatonin membrane receptor-dependent autophagy may be strategy for treatment of tongue squamous cell carcinoma [98] .

Several studies indicate that melatonin may induce apoptosis in cancer cells through inhibiting autophagy pathway. Melatonin down-regulates Beclin-1 and p62 expressions and LC3B-II/LC3B-I ratio in colitis-associated colon carcinogenesis in mice; this effect is associated with the increased level of Nrf2 and its downstream antioxidant enzymes including NAD(P)H:quinone oxidoreductase (NQO-1) and heme oxygenase-1 (HO-1). These suggest that the ameliorative effect of melatonin on inflammation and oxidative stress results in the reduction of autophagy [99] . Induction of ER stress is associated with the activation of autophagy in sorafenib-treated hepatocellular carcinoma cells, which this contributes to the resistance of cancer cells to apoptosis. Combination of melatonin with sorafenib inhibits ER stress-related autophagy through suppressing the PERK-ATF4-Beclin1 pathway leading to the sensitivity of hepatocellular carcinoma cells to sorafenib [76] . Co-stimulation of cancer cells with cisplatin and melatonin induce apoptosis in HeLa cells, which this effect is accompanied by inactivating mitophagy via blockade of JNK/Parkin pathway [100] . In contrast with this report, melatonin has been found to reversed the effects of cisplatin in HepG2 cells through suppression of mTOR and DNA excision repair cross complementary 1 (ERCC1) proteins expressions and upregulation of Beclin-1 and LC3II expressions [101] . Taken together, different effects of melatonin on autophagy may be related to type of cancer cells, the stage of cancer and dose of melatonin (Table 4 ).

The balance between cell proliferation and death in tissues is maintained by apoptosis, a classical form of programmed cell death. Apoptosis is associated with the disassembly of apoptotic cells into membrane-enclosed vesicles, which are removed by macrophages without inducing inflammatory responses. Apoptosis is mediated by two principle signaling pathways, including extrinsic and intrinsic pathways [102] . The extrinsic apoptotic signaling pathways, defined as death receptor pathways, are initiated by the interaction of transmembrane death receptors (Fas, TNFR1, DR4 and DR5) with extracellular ligands (FasL, TNFα, TRAIL, and TNFSF10) resulting in the activation of adaptor proteins such as Fas-associated death domain (FADD). Activated FADD recruits initiator caspases (caspase 8 and caspase 10) to form the death-inducing signal complex (DISC). Formation of DISC leads to the proteolytic activation of caspase 8, which is the main initiator caspase of the extrinsic apoptotic signaling pathway. Caspase 8 activates executioner caspases (caspase 3, caspase 6, and caspase 7) and cleaves Bid, a BH3-only domain member of the B cell lymphoma-2 (Bcl-2) family. Truncated Bid (tBid) translocates to mitochondria and activates other proapoptotic Bcl-2 family members including Bak or Bax [102, 103] .

The intrinsic apoptosis pathway, defined as mitochondrial-mediated apoptotic pathway, is activated by exogenous and endogenous stimuli such as DNA damage, oxidative stress, chemotherapy and radiotherapy. This apoptosis pathway is mediated by insertion of pro-apoptotic Bcl-2 family members (Bax/Bak) into mitochondrial membrane leading to the mitochondrial outer membrane permeabilization and release of pro-apoptotic factors such as cytochrome c, Smac/DIABLO, the nuclease EndoG, the oxidoreductase AIF, and the protease HtrA2/ Omi [104] . Therefore, activation of pro-apoptotic Bcl-2 family members (Bax/Bak) is essential for cancer therapy. In contrast, elevation of anti-apoptotic Bcl-2 family proteins inhibits apoptosis in cancer cells through heterodimerization with Bax/Bak preventing the release of pro-apoptotic factors from mitochondria; this could result in the resistance of cancer cells to immune-surveillance [105, 106] . Once in the cytosol, cytochrome c combines with Apaf-1 and procaspase-9 to drive the assembly of the apoptosome; this molecular platform activates caspase 9, which this is followed by the activation of caspase-3 cascade of apoptosis [107] . Smac/ DIABLO and HtrA2/Omi induce apoptosis through degrading inhibitor of apoptosis protein (IAP) family, neutralizing the inhibitory effect of IAPs on caspases [108] . The nuclease EndoG and the oxidoreductase AIF translocate to the nucleus, where they trigger internucleosomal DNA fragmentation independently of caspases [109] .

As mentioned earlier, UPR signaling may promote the apoptotic pathways. Upon ER stress, apoptosis signalregulating kinase 1 (ASK1) is recruited by IRE1α-TNF receptor-associated factor 2 (TRAF2) complex, causing activation of ASK1 and the downstream JNK pathway. Activation of JNK results in the phosphorylation of Bcl-2 and Bax; phosphorylation of Bcl-2 family suppresses antiapoptotic activity of Bcl-2, while induces mitochondrial translocation of Bax and activation of apoptosis pathway. Activated JNK also activates C/EBP homologous protein (CHOP), a stress-induced transcription factor inducing the expression of pro-apoptotic Bcl-2 family members. Furthermore, IRE1α-TRAF2 complex triggers the activation of caspase-12, which this caspase translocates from the ER to the cytosol, where it activates caspase-9, independent from the apoptosome pathway [110] . Furthermore, Activated PERK phosphorylates eIF2α, promoting the expression of activating transcriptional factor 4 (ATF4); ATF4 translocates to the nucleus where it induces CHOP expression [111] .

Melatonin is reported to restrict tumor growth and cancer cell proliferation through inducing apoptosis in cancer cells ( Table 5) . As a powerful antioxidant melatonin inhibits ROS-induced activation of extracellular-regulated protein kinases (ERKs) and Akt pathways which are involved in the cancer cell survivor; inactivation of ROS-dependent Akt signaling contributes to the down-regulation of cyclin N2a-allografted nude mice [193] Head and neck squamous cell carcinoma [191] D1, PCNA, and Bcl-2 and up-regulation of Bax in cancer cells [48] . Inhibition of MDM2 expression is a mechanism by which melatonin induces apoptosis through upregulating the activity of caspase-3 and -9; MDM2 is an E3 ubiquitin ligase, which negatively regulates the p53 tumor suppressor [112, 113] . Under hypoxic conditions, tumor cells become resistant to TRAIL-induced cell apoptosis; this contributes to the up-regulation of anti-apoptotic protein expression and reduction of pro-apoptotic protein expression. Treatment with melatonin blocks hypoxic responses leading to the induction of apoptosis in TRAIL resistance tumor cells by the regulation of mitochondrial transmembrane potential and induction of Bax translocation [114] . Melatonin inhibits cancer cell growth by increasing cell cycle arrest in the G2/M phase, which this effect is coincident with the induction of apoptosis through up-regulating the expression of p53, p21, caspase-3/8/9, PARP, cytochrome c, Bax, JNK 1,-2 and -3 and p38 MAPKs in cancer cells [115] . Melatonin triggers two distinct apoptotic processes including TGFβ1 and caspase-independent early apoptosis and TGFβ1 and caspases-dependent late apoptosis. Early apoptosis is associated with the elevation level of p53/MDM2 ratio and up-regulation of AIF release; this process is independent to caspase activity or cleavage of PARP. Late apoptosis is associated with elevation of caspases-9 and -7 activity and cleaved-PARP level as well as reduction of Bcl-2/Bax ratio [116] . Melatonin also induces apoptosis through simultaneous suppression of COX-2/ PGE2, p300/NF-κB, and PI3K/Akt signaling pathway. Inhibition of these pathways leads to the induction of Apaf-1 expression triggering cytochrome c release, and caspase-3 and -9 activation and cleavage [32] . Melatonin induces dephosphorylation and nuclear import of histone deacetylase 4 (HDAC4) in cancer cells; melatonin exerts this effect through inactivation of Ca 2+ / calmodulin-dependent protein kinase II alpha (CaMKIIα), leading to the H3 acetylation on Bcl-2 promoter and subsequent reduction of Bcl-2 expression [117] . Furthermore, inhibition of HDAC9 expression is a mechanism of melatonin to promote apoptosis in non-small cell lung cancer; the increased level of HDAC9 in patients with non-small cell lung cancer is correlated with worse overall survival and poor prognosis [118] . Melatonin promotes TNF-αmediated apoptosis via inhibiting mitophagy in tumor cells. Since activation of mitophagy suppresses mitochondrial apoptosis, inhibition of mitophagy by melatonin results in the repression of mitochondrial potential, elevation of ROS generation, augmentation of mPTP opening rate and upregulation of cytochrome c expression and caspases activity. Melatonin inhibits autophagy in tumor cells through inhibiting CaMKII activity leading to the suppression of Parkin expression [119] . In diethylnitrosamine (DEN)induced hepatocellular carcinoma (HCC), melatonin increases therapeutic potential of mesenchymal stem cells (MSCs) through reduction of oxidative stress and inflammation, and induction of apoptosis [120] .

Melatonin has been reported to increase therapeutic potential of anti-cancer agents, which this effect may result from its stimulatory effect on apoptosis. Co-treatment of melatonin and pterostilbene in colorectal cancer cells synergically enhances ROS production and apoptosis. Combination of these two agents upregulates the mRNA level of miR-25-5p, which this results in the activation of PARP and sex-determining region Y-Box10 (SOX10), and attenuation of Bcl-xL, neural precursor cell expressed developmentally downregulated protein 9 (NEDD9), and SOX9 expressions [121] . Melatonin synergically enhances anticancer potential of cisplatin through inducing apoptosis; melatonin increases the effect of cisplatin to the inhibition of ERK phosphorylation and induction of 90-kDa ribosomal S6 kinase (p90RSK) and heat shock protein 27 (HSP27) dephosphorylation [122] . Treatment with melatonin enhances ER stress-mediated apoptosis in tunicamycin-treated cancer cells; this effect is associated with the down-regulation of COX-2 and Bcl-2 expressions and up-regulation of Bim, CHOP and Bax expressions [73] . Melatonin inhibits tunicamycin-induced COX-2 activation in tumor cells through inhibiting NF-ĸB and p38 MAPK activation and p65 nuclear translocation [123] . Combination of melatonin with phenylarsine oxide also induces endoplasmic reticulum stress-induced cell death, accompanied by JNK activation, PARP cleavage, ROS generation and caspase-3 activation [124] .

This review summarizes the anti-carcinogenic potentials of melatonin by evaluating various signaling pathways. Melatonin inhibits proliferation of cancer cells through triggering cell cycle arrest and causes cell death by induction of apoptosis. Melatonin suppresses metastasis angiogenesis, and proliferation of cancer cells through affecting various signaling pathways in tumor cells. Melatonin also regulates autophagy pathway in cancer cell by affecting oxidative stress condition in tumor cells. These findings suggest that melatonin may increase the sensitivity of cancer cells to anti-cancer agents and may be a potential treatment for cancers either alone or in combination with other anti-cancer drugs. However, further clinical studies are needed to clarify the effect of this molecule in different cancers and obtain affective dose of melatonin for patients with cancer.

Abbreviations JNK: C-Jun N-terminal kinase; ROS: Reactive oxygen species; VEGF: Vascular endothelial growth factor; TNF-α: Tumor necrosis factor-α; IL-2: Interleukin-2; Nrf2: Nuclear factor erythroid 2-related factor 2; Apaf-1: Apoptotic protease activating factor-1; COX-2: Cyclooxygenase-2; Sirt1: Sirtuin; HIF: Hypoxiainducible factor; TRAIL: TNF-related apoptosis-inducing ligand; PARP-1: Poly [ADP-ribose] polymerase 1; ATG : Autophagy related genes; IRE1: Inositolrequiring enzyme 1; ATF6: Activating transcription factor 6; ERK: Extracellular signal-regulated kinase; MEK: Mitogen-activated protein kinase kinase; MAPK: Mitogen-activated protein kinase; CHOP: CCAAT-enhancer-binding proteins homologous protein; PUMA: P53-upregulated modulator of apoptosis; Bcl-2: B cell lymphoma-2; Bim: Bcl-2-interacting mediator of cell death; PI3K: Phosphatidylinositol-3-kinase; Akt: Protein kinase B; UPR: Unfolded protein response; ATF6α: Activating transcription factor 6α; ER: Endoplasmic reticulum; PERK: Protein kinase RNA-like ER kinase; ERK: Extracellular signal-regulated kinase; SPHK1: Sphingosine kinase 1; IFN-γ: Interferon-gamma; PGC1A: Peroxisome proliferator-activated receptor gamma coactivator 1A; NQO-1: NAD(P) H:quinone oxidoreductase; HO-1: Heme oxygenase-1; FADD: Fas-associated death domain; tBid: Truncated Bid; ASK1: Apoptosis signal-regulating kinase 1; TRAF2: IRE1α-TNF receptor-associated factor 2; ERKs: Extracellular-regulated protein kinases; CaMKIIα: Ca 2+ /calmodulin-dependent protein kinase II alpha; DEN: Diethylnitrosamine; HCC: Hepatocellular carcinoma; MSCs: Mesenchymal stem cells; NEDD9: Neural precursor cell expressed developmentally downregulated protein 9; p90RSK: 90-KDa ribosomal S6 kinase; HSP27: Heat shock protein 27.

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Clinical application of melatonin in the treatment of cardiovascular diseases: current evidence and new insights into the cardioprotective and cardiotherapeutic properties

Melatonin and mammary cancer: a short review

Melatonin and mammary pathological growth

Influence of melatonin on invasive and metastatic properties of MCF-7 human breast cancer cells

Tumorigenesis and the angiogenic switch

The role of hypoxia-induced factors in tumor progression

Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer

Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation

Melatonin: an atypical hormone with major functions in the regulation of angiogenesis

Role of melatonin in controlling angiogenesis under physiological and pathological conditions

Melatonin suppresses tumor angiogenesis by inhibiting HIF-1alpha stabilization under hypoxia

Sphingosine kinase 1 pathway is involved in melatonin-induced HIF-1α inactivation in hypoxic PC-3 prostate cancer cells

Regulation of vascular endothelial growth factor by melatonin in human breast cancer cells

Melatonin and prostate cancer cell proliferation: interplay with castration, epidermal growth factor, and androgen sensitivity

Melatonin inhibits reactive oxygen species-driven proliferation, epithelial-mesenchymal transition, and vasculogenic mimicry in oral cancer

Role of transforming growth factor β1 in the inhibition of gastric cancer cell proliferation by melatonin in vitro and in vivo

Melatonin reduces endothelin-1 expression and secretion in colon cancer cells through the inactivation of FoxO-1 and NF-κβ

Molecular markers of angiogenesis and metastasis in lines of oral carcinoma after treatment with melatonin

Melatonin regulates angiogenic and inflammatory proteins in MDA-MB-231 cell line and in co-culture with cancer-associated fibroblasts

Melatonin downregulates nuclear receptor RZR/RORγ expression causing growth-inhibitory and anti-angiogenesis activity in human gastric cancer cells in vitro and in vivo

Antiangiogenic activity of melatonin in advanced cancer patients

Melatonin regulates tumor angiogenesis via miR-424-5p/VEGFA signaling pathway in osteosarcoma

Some current insights into oxidative stress

The value of serum total oxidant to the antioxidant ratio as a biomarker of knee osteoarthritis

Correlation between oxidative stress, nutrition, and cancer initiation

Oxidative stress, inflammation, and cancer: how are they linked?

Melatonin: a well-documented antioxidant with conditional pro-oxidant actions

Melatonin as a natural ally against oxidative stress: a physicochemical examination

Melatonin for the prevention and treatment of cancer

Melatonin inhibits oxidative stress and apoptosis in cryopreserved ovarian tissues via Nrf2/HO-1 signaling pathway

Antioxidants maintain cellular redox homeostasis by elimination of reactive oxygen species

Unfolded protein response of the endoplasmic reticulum in tumor progression and immunogenicity

Here, there, and everywhere: the importance of ER membrane contact sites

Endoplasmic reticulum stress: its role in disease and novel prospects for therapy

Endoplasmic reticulum stress and the inflammatory basis of metabolic disease

Mitochondrial dysfunction in age-related macular degeneration: melatonin as a potential treatment

Cancer and ER stress: Mutual crosstalk between autophagy, oxidative stress and inflammatory response

Melatonin promotes apoptosis of colorectal cancer cells via superoxide-mediated ER stress by inhibiting cellular prion protein expression

Melatonin-mediated intracellular insulin during 2-deoxy-d-glucose treatment is reduced through autophagy and EDC3 protein in insulinoma INS-1E cells

Melatonin sensitizes human hepatoma cells to endoplasmic reticulum stress-induced apoptosis

Melatonin, a novel selective ATF-6 inhibitor, induces human hepatoma cell apoptosis through COX-2 downregulation

Melatonin activates endoplasmic reticulum stress and apoptosis in rats with diethylnitrosamine-induced hepatocarcinogenesis

Melatonin increases the sensitivity of hepatocellular carcinoma to sorafenib through the PERK-ATF4-beclin1 pathway

The therapeutic effect of melatonin on GC by inducing cell apoptosis and autophagy induced by endoplasmic reticulum stress

Melatonin-mediated insulin synthesis during endoplasmic reticulum stress involves HuD expression in rat insulinoma INS-1E cells

Melatonin reverses tunicamycin-induced endoplasmic reticulum stress in human hepatocellular carcinoma cells and improves cytotoxic response to doxorubicin by increasing CHOP and decreasing survivin

Atorvastatin attenuates bleomycin-induced pulmonary fibrosis via suppressing iNOS expression and the CTGF (CCN2)/ERK signaling pathway

Mammalian autophagy: how does it work?

Autophagy: cellular and molecular mechanisms

Mechanisms of autophagy

Cargo recognition and trafficking in selective autophagy

Crosstalk of autophagy and apoptosis: Involvement of the dual role of autophagy under ER stress

The eIF2alpha/ATF4 pathway is essential for stress-induced autophagy gene expression

ER stress (PERK/eIF2alpha phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation

XBP1 mRNA splicing triggers an autophagic response in endothelial cells through BECLIN-1 transcriptional activation

Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy

BCL-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G(2)/M

Control of macroautophagy by calcium, calmodulin-dependent kinase kinasebeta, and Bcl-2

Phosphorylation of Beclin 1 by DAP-kinase promotes autophagy by weakening its interactions with Bcl-2 and Bcl-XL

Melatonin enhances cisplatin and radiation cytotoxicity in head and neck squamous cell carcinoma by stimulating mitochondrial ROS generation, apoptosis, and autophagy

Combination of melatonin and rapamycin for head and neck cancer therapy: Suppression of AKT/mTOR pathway activation, and activation of mitophagy and apoptosis via mitochondrial function regulation

Melatonin/PGC1A/UCP1 promotes tumor slimming and represses tumor progression by initiating autophagy and lipid browning

Ceramide metabolism regulates autophagy and apoptotic cell death induced by melatonin in liver cancer cells

Inhibition of autophagy triggers melatonininduced apoptosis in glioblastoma cells

Inhibiting MT2-TFE3-dependent autophagy enhances melatonininduced apoptosis in tongue squamous cell carcinoma

Melatonin modulated autophagy and Nrf2 signaling pathways in mice with colitis-associated colon carcinogenesis

Melatonin increases human cervical cancer HeLa cells apoptosis induced by cisplatin via inhibition of JNK/Parkin/ mitophagy axis

Melatonin attenuates cisplatin-induced HepG2 cell death via the regulation of mTOR and ERCC1 expressions

Apoptosis in pulmonary fibrosis: too much or not enough?

Cleavage by Caspase 8 and mitochondrial membrane association activate the BH3-only protein bid during TRAIL-induced apoptosis

Apoptotic cell death regulation in neurons

Heterodimerization of Bcl-2 and Bcl-X(L) with Bax and Bad in colorectal cancer

Targeting the Bcl-2 family for cancer therapy

Evolving concepts of apoptosis in idiopathic pulmonary fibrosis

Mitochondrial protease Omi/HtrA2 enhances caspase activation through multiple pathways

Apoptosis-inducing factor: structure, function, and redox regulation

Anti-cancer natural products and their bioactive compounds inducing ER stress-mediated apoptosis: a review

Upregulation of CHOP/GADD153 during coronavirus infectious bronchitis virus infection modulates apoptosis by restricting activation of the extracellular signal-regulated kinase pathway

Downregulation of AKT and MDM2, melatonin induces apoptosis in AGS and MGC803 Cells

Melatonin downregulates MDM2 gene expression and enhances p53 acetylation in MCF-7 cells

Overcoming hypoxic-resistance of tumor cells to TRAIL-induced apoptosis through melatonin

Melatonin induces cell cycle arrest and apoptosis in hepatocarcinoma HepG2 cell line

Evidence for a biphasic apoptotic pathway induced by melatonin in MCF-7 breast cancer cells

Melatonin induces apoptosis of colorectal cancer cells through HDAC4 nuclear import mediated by CaMKII inactivation

Histone deacetylase 9 downregulation decreases tumor growth and promotes apoptosis in non-small cell lung cancer after melatonin treatment

Melatonin enhances TNF-alpha-mediated cervical cancer HeLa cells death via suppressing CaMKII/Parkin/mitophagy axis

Melatonin maximizes the therapeutic potential of non-preconditioned MSCs in a DEN-induced rat model of HCC

NEDD9 inhibition by miR-25-5p activation is critically involved in co-treatment of melatonin-and pterostilbene-induced apoptosis in colorectal cancer cells

Melatonin synergistically enhances cisplatin-induced apoptosis via the dephosphorylation of ERK/p90 ribosomal S6 kinase/heat shock protein 27 in SK-OV-3 cells

Melatonin-mediated Bim up-regulation and cyclooxygenase-2 (COX-2) down-regulation enhances tunicamycin-induced apoptosis in MDA-MB-231 cells

Melatonin triggers the anticancer potential of phenylarsine oxide via induction of apoptosis through ROS generation and JNK activation

Complementary actions of melatonin on angiogenic factors, the angiopoietin/Tie2 axis and VEGF, in cocultures of human endothelial and breast cancer cells

Amelioration of Dalton's lymphoma-induced angiogenesis by melatonin

Melatonin reduces angiogenesis in serous papillary ovarian carcinoma of ethanol-preferring rats

Melatonin and IL-25 modulate apoptosis and angiogenesis mediators in metastatic (CF-41) and non-metastatic (CMT-U229) canine mammary tumour cells

Melatonin inhibits angiogenesis in SH-SY5Y human neuroblastoma cells by downregulation of VEGF

Melatonin downregulates nuclear receptor RZR/RORgamma expression causing growth-inhibitory and anti-angiogenesis activity in human gastric cancer cells in vitro and in vivo

Pires de Campos Zuccari DA. Melatonin regulates angiogenic factors under hypoxia in breast cancer cell lines

Propionibacterium acnes augments antitumor, antiangiogenesis and immunomodulatory effects of melatonin on breast cancer implanted in mice

Upregulation of miRNA3195 and miRNA374b mediates the anti-angiogenic properties of melatonin in hypoxic PC-3 prostate cancer cells

Inhibition of VEGF expression through blockade of Hif1alpha and STAT3 signalling mediates the anti-angiogenic effect of melatonin in HepG2 liver cancer cells

Melatonin suppresses tumor progression by reducing angiogenesis stimulated by HIF-1 in a mouse tumor model

Effect of melatonin on tumor growth and angiogenesis in xenograft model of breast cancer

Melatonin restrains angiogenic factors in triple-negative breast cancer by targeting miR-152-3p: In vivo and in vitro studies

Therapeutic potential of melatonin in the regulation of MiR-148a-3p and angiogenic factors in breast cancer

Effects of miR-34b/miR-892a upregulation and inhibition of ABCB1/ABCB4 on melatonin-induced apoptosis in VCR-resistant oral cancer cells

A ketogenic diet combined with melatonin overcomes cisplatin and vincristine drug resistance in breast carcinoma syngraft

Ameliorative effects of melatonin against solid Ehrlich carcinoma progression in female mice

Melatonin synergizes BRAF-targeting agent vemurafenib in melanoma treatment by inhibiting iNOS/hTERT signaling and cancer-stem cell traits

Melatonin regulates tumor aggressiveness under acidosis condition in breast cancer cell lines

Melatonin and its metabolite N1-acetyl-N2-formyl-5-methoxykynuramine (afmk) enhance chemosensitivity to gemcitabine in pancreatic carcinoma cells

Effects of melatonin on apoptosis and cell differentiation in MCF-7 derived cancer stem cells

Melatonin can strengthen the effect of retinoic acid in HL-60 cells

Synergistic effect of thymoquinone and melatonin against breast cancer implanted in mice

Stimulatory effect of indolic hormone on As2O3 cytotoxicity in breast cancer cells: NF-kappaB-dependent mechanism of action of melatonin

Melatonin synergizes with sorafenib to suppress pancreatic cancer via melatonin receptor and PDGFR-beta/STAT3 Pathway

Mitochondria transcription factor A: a putative target for the effect of melatonin on u87mg malignant glioma cell line

Hyperbaric oxygen treatment sensitizes gastric cancer cells to melatonin-induced apoptosis through multiple pathways

Melatonin suppresses thyroid cancer growth and overcomes radioresistance via inhibition of p65 phosphorylation and induction of ROS

Melatonin induces the apoptosis and inhibits the proliferation of human gastric cancer cells via blockade of the AKT/MDM2 pathway

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

Melatonin inhibits the proliferation of gastric cancer cells through regulating the miR-16-5p-Smad3 pathway

Melatonin-induced changes in cytosolic calcium might be responsible for apoptosis induction in tumour cells

Antiproliferative and pro-apoptotic activity of melatonin analogues on melanoma and breast cancer cells

Melatonin potentiates the antitumor effect of curcumin by inhibiting IKKbeta/NF-kappaB/COX-2 signaling pathway

Melatonin increases the effect of 5-fluorouracil-based chemotherapy in human colorectal adenocarcinoma cells in vitro

Melatonin inhibits AP-2beta/hTERT, NF-kappaB/COX-2 and Akt/ERK and activates caspase/Cyto C signaling to enhance the antitumor activity of berberine in lung cancer cells

Melatonin induces cell apoptosis in AGS Cells through the activation of JNK and P38 MAPK and the suppression of nuclear Factor-Kappa B: a novel therapeutic implication for gastric cancer

Apoptosis is triggered by melatonin in an in vivo model of ovarian carcinoma

Melatonin sensitizes human cervical cancer HeLa cells to cisplatin-induced cytotoxicity and apoptosis: effects on oxidative stress and DNA fragmentation

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

Comparison of the effects of 13-cis retinoic acid and melatonin on the viabilities of SH-SY5Y neuroblastoma cell line

Melatonin induces apoptosis in cholangiocarcinoma cell lines by activating the reactive oxygen species-mediated mitochondrial pathway

Melatonin potentiates cisplatin-induced apoptosis and cell cycle arrest in human lung adenocarcinoma cells

Anti-gastric cancer effect of melatonin and Bcl-2, Bax, p21 and p53 expression changes. Sheng li xue bao

Melatonin induces apoptosis through biomolecular changes, in SK-LU-1 human lung adenocarcinoma cells

CCAR2 deficiency augments genotoxic stressinduced apoptosis in the presence of melatonin in non-small cell lung cancer cells

Melatonin treatment induces interplay of apoptosis, autophagy, and senescence in human colorectal cancer cells

Transcriptional and post-translational regulation of Bim controls apoptosis in melatonin-treated human renal cancer Caki cells

Melatonin induces apoptosis through a caspase-dependent but reactive oxygen species-independent mechanism in human leukemia Molt-3 cells

Melatonin inhibits cell growth and migration, but promotes apoptosis in gastric cancer cell line

Melatonin potentiates the antiproliferative and pro-apoptotic effects of ursolic acid in colon cancer cells by modulating multiple signaling pathways

Melatonin is involved in the apoptosis and necrosis of pancreatic cancer cell line SW-1990 via modulating of Bcl-2/Bax balance

Melatonin treatment induces apoptosis through regulating the nuclear factor-kappaB and mitogen-activated protein kinase signaling pathways in human gastric cancer SGC7901 cells

Melatonin inhibits proliferation and invasion via repression of miRNA-155 in glioma cells

Efficacy of melatonin, IL-25 and siIL-17B in tumorigenesis-associated properties of breast cancer cell lines

Melatonin enhances hydrogen peroxide-induced apoptosis in human promyelocytic leukaemia HL-60 cells

Melatonin sensitizes Caki renal cancer cells to kahweol-induced apoptosis through CHOP-mediated up-regulation of PUMA

Melatonin induces pro-apoptotic signaling pathway in human pancreatic carcinoma cells (PANC-1)

Synergistic antitumor effect of melatonin with several chemotherapeutic drugs on human Ewing sarcoma cancer cells: potentiation of the extrinsic apoptotic pathway

Melatonin research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year submit your research ? Choose BMC and benefit from: ? Choose BMC and benefit from: sensitizes human malignant glioma cells against TRAIL-induced cell death

Melatonin exerts differential actions on X-ray radiation-induced apoptosis in normal mice splenocytes and Jurkat leukemia cells

Alterations in mitochondrial respiratory functions, redox metabolism and apoptosis by oxidant 4-hydroxynonenal and antioxidants curcumin and melatonin in PC12 cells

Melatonin induces apoptosis in human neuroblastoma cancer cells

A comparison of the action of amifostine and melatonin on DNA-damaging effects and apoptosis induced by idarubicin in normal and cancer cells

Melatonin potentiates flavone-induced apoptosis in human colon cancer cells by increasing the level of glycolytic end products

Does melatonin induce apoptosis in MCF-7 human breast cancer cells in vitro?

Melatonin enhances sensitivity to fluorouracil in oesophageal squamous cell carcinoma through inhibition of Erk and Akt pathway

Melatonin activates cell death programs for the suppression of uterine leiomyoma cell proliferation

Melatonin promotes neuroblastoma cell differentiation by activating hyaluronan synthase 3-induced mitophagy

Melatonin reverses H(2) O(2) -induced senescence in SH-SY5Y cells by enhancing autophagy via sirtuin 1 deacetylation of the RelA/p65 subunit of NF-κB

Involvement of autophagy in melatonin-induced cytotoxicity in glioma-initiating cells

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

The smart molecule that differentially modulates autophagy in tumor and normal placental cells

Melatonin limits paclitaxel-induced mitochondrial dysfunction in vitro and protects against paclitaxel-induced neuropathic pain in the rat

Melatonin pre-treatment mitigates SHSY-5Y cells against oxaliplatin induced mitochondrial stress and apoptotic cell death

Synergic effects of doxorubicin and melatonin on apoptosis and mitochondrial oxidative stress in MCF-7 breast cancer cells: involvement of TRPV1 channels

Immunomodulatory effect of melatonin in SK-LU-1 human lung adenocarcinoma cells co-cultured with peripheral blood mononuclear cells

Improvement of capecitabine antitumoral activity by melatonin in pancreatic cancer

Pharmacologic concentrations of melatonin have diverse influence on differential expressions of angiogenic chemokine genes in different hepatocellular carcinoma cell lines

Melatonin and celecoxib improve the outcomes in hamsters with experimental pancreatic cancer

Chemopreventive effect of lycopene alone or with melatonin against the genesis of oxidative stress and mammary tumors induced by 7,12 dimethyl(a)benzanthracene in sprague dawely female rats

Beneficial properties of melatonin in an experimental model of pancreatic cancer

Different effects of melatonin on X-rays-irradiated cancer cells in a dose-dependent manner

Melatonin-mediated downregulation of ZNF746 suppresses bladder tumorigenesis mainly through inhibiting the AKT-MMP-9 signaling pathway

Melatonin Enhances Palladium-Nanoparticle-Induced Cytotoxicity and Apoptosis in Human Lung Epithelial Adenocarcinoma Cells A549 and H1229. Antioxidants

Inadera H. Melatonin sensitises shikonin-induced cancer cell death mediated by oxidative stress via inhibition of the SIRT3/SOD2-AKT pathway

Melatonin triggers the anticancer potential of phenylarsine oxide via induction of apoptosis through ROS generation and JNK activation

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