Melatonin and Liver Cancer

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1		Paula Fernández-Palanca	+ 3643 word(s)	3643	2021-01-11 13:30:21	\|
2	format correct	Conner Chen	Meta information modification	3643	2021-10-12 05:38:13	\|

Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine with beneficial effects in a broad number of tumors, including the primary liver cancers hepatocarcinoma (HCC) and cholangiocarcinoma (CCA). Among them, melatonin has shown to modulate different cancer-associated processes and enhance drug efficacy against HCC and CCA. Therefore, melatonin has a potential role in improving the current therapeutic landscape in these liver tumors.

cholangiocarcinoma hepatocellular carcinoma liver cancer melatonin

1. Introduction

Primary liver cancer constitutes the sixth most prevalent type of tumor and is the fourth common cause of cancer-related mortality worldwide ^[1]. A total of 841,080 new cases were diagnosed in 2018, with an estimated 781,631 deaths and an age-standardized mortality rate of 8.5/100,000. The most frequent types of primary liver cancer in adults are hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), constituting HCC the 70-85% of cases and CCA the 30-15%, depending on the country ^[2]. Liver cancer also appears in children and adolescents, accounting hepatoblastoma (HB) and HCC for 67-80% and 20-33% of cases, respectively ^[2]^[3].

Unfortunately, most of the liver cancer patients are diagnosed in advanced stages when surgical treatment is not available ^[4]. Moreover, the high mortality associated with liver cancer is related to its lack of sensitivity and development of resistances to a few treatments that lead to the chemotherapy failure. These drawbacks may be explained, at least in part, by the various phenotypes and histological characteristics of tumor liver cells and its microenvironment ^[5]. Furthermore, the high refractoriness of liver cancer to treatments has been associated with the interaction of very complex and diverse mechanisms of chemoresistance, which can act synergistically to protect tumor cells from the chemotherapy agents ^[3].

Melatonin (N-acetyl-5-methoxytryptamine), the main product of the pineal gland, is an indoleamine with antioxidant, chronobiotic and anti-inflammatory properties ^[6]. A reduction of melatonin levels or a depressed excretion of its main metabolite, 6-sulfatoxymelatonin, have been related to an increased cancer risk, suggesting an anticancer role of this indoleamine ^[7]. Collectively, the published data strongly support the oncostatic actions of melatonin on different types of tumors, including liver cancer ^[8]^[9]^[10].

The inhibitory role of melatonin in hepatic tumors involves a number of different molecular and cellular processes including reduction of cellular proliferation, cell cycle arrest, limiting angiogenesis and metastasis and promoting cell death ^[10]^[11]^[12]^[13]^[14]^[15]^[16]^[17]. Moreover, melatonin reportedly increases the sensitivity of liver cancer cells to currently-available treatments ^[4]^[18], and as other natural compounds such as quercetin, curcumin and resveratrol, melatonin properties could ameliorate chemotherapeutic toxicity ^[19]^[20]^[21].

2. Antioxidant and chronobiotic actions of melatonin in liver cancer

Carcinogenetic processes often involve oxidative stress, and administration of antioxidant molecules may reduce the damage to cancerous hepatocytes ^[22]^[21]^[23]. Melatonin acts as an indirect antioxidant and as a direct free radical scavenger, and displays an important role as an immunomodulatory and chronobiotic agent in different tissues, including liver ^[6]^[14]^[24]^[25]. These effects have been observed in several studies carried out with both in vitro and in vivo models of HCC and CCA, where melatonin administration showed a markedly antioxidant activity by modulating expression and activity of antioxidant enzymes and oxidant agents ^[26]^[27]^[28]. However, under different conditions researches have reported an increase in oxidative stress derived from melatonin treatment in these liver tumors, which could be attributed to the employ of higher doses of this indoleamine ^[18]^[29]. Results found suggest that oxidative stress modulation by melatonin could be useful in the HCC and CAA treatment and prevention.

Since circadian clock plays a key role in liver physiology and chronodisruption is known to augment hepatocarcinogenesis ^[30], different experiments have been carried out to analyze the association between the antioxidant and chronobiotic effects of melatonin in HCC. During hepatocarcinogenesis it has been described the appearance of circadian rhythm perturbations that contribute to the establishment of liver tumors; however, melatonin has also found to be effective in restoring the normal rhythms not only as single treatment but also in combination with several drugs, such as oxaliplatin and α-ketoglutarate. This chronobiotic activity has been associated to the ability of melatonin to regulate the acrophase, mesor and amplitude parameters of lipid peroxidation and components of the antioxidant system, revealing an hepatoprotective action of melatonin derived from circadian rhythms modulation ^[31]^[32]^[33]^[34].

3. Cell cycle arrest by melatonin in liver cancer

Carcinogenesis is a multistage process usually promoted by a disturbed and uncontrolled cell proliferation, with cell cycle dysregulation, associated with an increase in tumor cell viability. In these events, melatonin involvement has also been described since several studies reported cell cycle arrest after administration of this indoleamine in HCC alone or in combination with several drugs, such as sorafenib and (-)-epigallocatechin-3-gallate (EGCG). Nonetheless, cytostatic effects of melatonin have been identified in different stages of cell cycle, some studies observed an arrest in G0/G1 phase and another in G2/M phase, while induction of p53 and decrease of cyclin D1 expression are mostly found ^[10]^[35]^[36]^[37]^[38]^[39]^[40]. In this line, melatonin also acts through the melatonin receptors MT1, MT3 and retinoic acid-related orphan receptor alpha (RORα) to arrest cell cycle and inhibit cell proliferation by increasing receptors expression not only in HCC but also in CCA ^[11]^[12]^[41]. Another relevant molecules involved in cell cycle modulation, the brain and muscle arnt-like protein 1 (Bmal1) and the circadian locomotor output cycles protein kaput (Clock) proteins, have been also reported to be modulated by melatonin in HCC ^[14]. Altogether, these results highlight the potential of melatonin as a cytostatic agent in the treatment of liver tumors.

4. Apoptosis modulation by melatonin in liver cancer

Apoptosis is a cellular mechanism of programmed cell death which is involved in numerous diseases, including cancer. Resistance to apoptosis is one of the main hallmarks of cancer and selective induction of this type of cell death in cancer cells has emerged as an interesting possibility for new antitumor treatments ^[42]. In liver, apoptotic signaling is transduced mainly via two molecular pathways: the extrinsic or death receptor-mediated pathway and the intrinsic or mitochondria-dependent pathway. Although the extrinsic pathway is induced by death ligands located in the cellular membrane and the intrinsic pathway is initiated as consequence of mitochondria dysfunction, both concur in a common finnal stage ^[42]^[43].

Melatonin effects on apoptosis modulation have been broadly studied in liver tumors. In both cellular and animal models, melatonin has demonstrated to be a powerful proapoptotic agent by inducing the extrinsic and the intrinsic pathway not only in HCC but also in CCA ^[10]^[14]^[44]^[45]^[29]^[46]. Moreover, several signaling pathways have been identified as mechanisms responsible for melatonin-derived apoptosis induction, such as promotion of endoplasmic reticulum (ER) stress, activation of NF-κB pathway and reduction of oxidative and nitrosative stress by melatonin ^[17]^[45]^[46]^[47]^[48]. Proapoptotic effects of melatonin have been also found when combined with other compounds, such as doxorubicin, cisplatin, sorafenib, regorafenib, 5-fluorouracil and EGCG, where coadministration with melatonin led to a higher induction of apoptosis and chemosensitivity ^[39]^[40]^[49]^[50]^[51]^[52]^[53]^[54]^[55]^[56].

5. Melatonin regulation of autophagy in liver cancer

The process of autophagy constitutes a bulk degradation system with a key role in the maintenance of cellular homeostasis in order to promote adaptation and cell survival. Nevertheless, when there is a excessive stimulation, programmed cell death is induced instead of survival in a number of different pathophysiological situations including tumorigenesis ^[57]. Therefore, in cancer cells autophagy can act as a double-edged sword removing malignant cells and damaged mitochondria at the early stages, but inducing survival under hypoxia and ischemia conditions in the later phases, which can be also associated with chemotherapy resistance and tumor progression ^[18].

As the dual role of autophagy, melatonin effects also depend on the cellular context, finding an autophagy induction in HCC when administered melatonin, which was diminishing the proapoptotic activity of the indoleamine, since disruption of autophagy promoted apoptosis ^[16]^[58]. Similarly, melatonin and cisplatin combined administration also induced an autophagy flux, improving antitumor effects of cisplatin ^[59]. However, coadministration of melatonin with sorafenib led to a reduction of the sorafenib-induced autophagy, promoting death of hepatocytes ^[60]^[61]. Furthermore, mitophagy, a selective degradation process of mitochondrias, is also modulated by melatonin. Results showed an increased mitophagy-associated apoptosis when combined with sorafenib under normoxic conditions, while after hypoxic induction melatonin and sorafenib treatment led to the inhibition of a cytoprotective mitophagy ^[4]^[18].

6. Inhibitory actions of melatonin on angiogenesis and invasion in liver cancer

Angiogenesis—the process of new blood-vessel growth from the existing vasculature—plays a key role facilitating tumor growth and the metastatic process and has been widely related with progression, invasion and metastasis of liver tumors ^[62]^[63]^[64].

The proangiogenic vascular endothelial growth factor (VEGF) along with the main regulator of hypoxia response, HIF-1α, are two major proteins involved in angiogenesis promotion. Melatonin has shown to impaired angiogenic and invasive abilities of liver cancer cells through inhibition of both VEGF and HIF-1α, as well as other related molecules, including STAT-3, the CBP/p300 co-activator, the forkhead box A2 (FOXA2) transcription factor expression, matrix metalloproteinase 9 (MMP-9) ^[13]^[15]^[65]^[66]^[67]. Curiously, long non-coding RNAs (lncRNA) and microRNAs (miRNA) have also been involved in this melatonin-derived antiangiogenic activity, such as lncRNA carbamoyl-phosphate synthase 1 intronic transcript 1 (lncRNA-CPS1-IT1), lncRNA RAD51 antisense RNA 1 (lncRNA RAD51-AS1) and miRNA let7i-p ^[66]^[68]^[69]. Regarding to proangiogenic and angiostatic chemokines, melatonin effects have not fully cleared, since contradictory results where observed in two HCC cell lines susceptible and resistant to amphotericin B (AmB). These findings indicate that clinical application of melatonin in patients with HCC should consider the liver tumor characteristics for the optimization of indole concentrations ^[70].

7. Immunomodulatory effects of melatonin in liver cancer

As previously indicated, melatonin acts as both antioxidant and chronobiotic but also as an immunomodulatory agent ^[6]^[14]^[24]^[25]. Some clinical results from case reports have shown that melatonin combination with immunotherapy impaired HCC progression and development of new liver tumors ^[71]. Additionally, preclinical studies exhibited interesting results where melatonin administration led to an increased immune response in both HCC and CCA models ^[72]^[73], in some cases accompanied by an anti-inflammatory activity ^[73].

All of these findings reporting antitumor actions of melatonin in the HCC and CCA liver tumors are summarized in Table 1.

Table 1. Basic characteristics of experimental studies evaluating antitumor effects of melatonin against liver tumors.

First Author, Publication Year, [Reference]	Country	Liver Tumor	Experimental Model (n, Sample Size per Group)	Administration Strategy	Treatment Regimen	Process Alteration
Dakshayani et al. 2005 ^[26]	India	HCC	In vivo Adult male Wistar rats Intraperitoneal injection of DEN followed by subcutaneous CCl₄ (n = 6)	Intraperitoneal melatonin	5 mg/kg 20 weeks	Antioxidant and hepatoprotective activity
Dakshayani et al. 2007 ^[31]	India	HCC	In vivo Adult male Wistar rats Intraperitoneal injection of DEN followed by subcutaneous CCl₄ (n = 6)	Intraperitoneal melatonin	5 mg/kg Thrice a week 20 weeks	Chronobiotic effect Antioxidant effect
Subramanian et al. 2007 ^[27]	India	HCC	In vivo 3-months-old male Wistar rats Intraperitoneal injection of DEN followed by subcutaneous of CCl₄ (n = 6)	Intraperitoneal melatonin	5 mg/kg Daily 20 weeks	Tumor growth inhibition Antioxidant activity
Martín-Renedo et al. 2008 ^[10]	Spain	HCC	In vitro Human HepG2 cell line	Melatonin	0.1–10 mM 4, 6, 8 and 10 days	Proliferation inhibition Apoptosis induction Cell cycle arrest
Subramanian et al. 2008 ^[32]	India	HCC	In vivo 3-months-old male Wistar rats Intraperitoneal injection of DEN followed by subcutaneous injection of CCl₄ (n = 6)	Intraperitoneal melatonin	5 mg/kg Daily 20 weeks	Chronobiotic effect Antioxidant effect
Carbajo-Pescador et al. 2009 ^[11]	Spain	HCC	In vitro Human HepG2 cell line	Melatonin	1–2.5 mM 2, 4 and 6 days	Proliferation inhibition Cell cycle arrest
Ozdemir et al. 2009 ^[35]	Turkey	HCC	In vitro Human HepG2 cell line	Melatonin	0.05–1 mM 72 h	Cell cycle arrest
Fan et al. 2010 ^[49]	China	HCC	In vitro Human HepG2 and Bel-7402 cell lines	Melatonin + Doxorubicin	0.01–10 µM 48 h	Proliferation inhibition Apoptosis induction
Laothong et al. 2010 ^[28]	Thailand	CCA	In vivo Male Syrian golden hamsters Oral inoculation of 50 metacercariae of Opisthorchis viverrini (n = 5)	Oral melatonin	5, 10, 20 mg/kg Daily 30 days	Antioxidant and protective activity
Lin and Chuang 2010 ^[70]	Taiwan	HCC	In vitro Human HCC cell lines: HCC24/KMUH (resistant to AmB-induced oxidative stress) and HCC38/KMUH: (susceptible to AmB-induced oxidative stress)	Melatonin	1 and 100 µM 24 h	Proliferation increase
Lin and Chuang 2010 ^[70]	Taiwan	HCC		Melatonin + AmB	1 and 100 µM 24 h	Antiangiogenic effect
Carbajo-Pescador et al. 2011 ^[12]	Spain	HCC	In vitro Human HepG2 cell line	Melatonin	1–2.5 mM 12, 24 and 48 h	Proliferation inhibition
Han et al. 2011 ^[41]	New York	CCA	In vivo 6-weeks-old male BALB/c nude mice Subcutaneous injection of Mz-ChA-1 cells (n = 4)	Intraperitoneal melatonin	4 mg/kg Thrice a week 43 days	Proliferation inhibition
Carbajo-Pescador et al. 2012 ^[44]	Spain	HCC	In vitro Human HepG2 cell line	Melatonin	50–2000 µM 1, 6, 24 and 48 h	Apoptosis induction
Cid et al. 2012 ^[36]	Spain	HCC	In vitro Human HepG2 cell line	Melatonin + MF exposure	0.01–1000 nM 4, 5 and 7 days	Proliferation inhibition
Liu et al. 2012 ^[58]	China	HCC	In vitro Mouse hepatoma cell line H22	Melatonin	100 µM 24 h	Apoptosis induction
			In vitro Mouse hepatoma cell line H22	Melatonin + Beclin-1 RNAi Melatonin + 3-MA	100 µM 24 h	Autophagy blockade Apoptosis induction
			In vivo 8-weeks-old female BALB/c mice Subcutaneous injection of H22 cells (n = 10)	Intraperitoneal melatonin	10 or 20 mg/kg Daily 14 days	Autophagy induction
Zha et al. 2012 ^[47]	China	HCC	In vitro Human HCC HepG2 cell line Human hepatocyte HL-7702 cell line	Melatonin + Tunicamycin	10⁻⁷ µM 24 h	Proliferation inhibition Apoptosis induction
Carbajo-Pescador et al. 2013 ^[13]	Spain	HCC	In vitro Human HepG2 cell line	Melatonin	1 nM and 1 mM 2, 4, 6, 8, 12 and 24 h or 24 h	Hypoxia-dependent angiogenesis
Fan et al. 2013 ^[50]	China	HCC	In vitro Human HepG2 and SMMC-7721 cell lines	Melatonin + Doxorubicin	1 mM 24 h	Apoptosis induction
Fan et al. 2013 ^[50]	China	HCC	In vitro Human HepG2 and SMMC-7721 cell lines	Melatonin + Doxorubicin + Tunicamycin	0.1–1000 µM 24 h	Proliferation inhibition Apoptosis induction
Fan et al. 2013b ^[51]	China	HCC	In vitro Human HepG2 and SMMC-7721 cell lines	Melatonin	0.001–1000 µM 24 and 48 h	Proliferation inhibition Apoptosis induction
Laothong et al. 2013 ^[45]	Thailand	CCA	In vivo 4-to-6-weeks-old male Syrian golden hamsters Oral inoculation of 50 metacercariae of Opisthorchis viverrini and 12.5 ppm DEN (n = 15)	Oral melatonin	10 or 50 mg/kg Daily 120 days	Apoptosis induction
Tomov et al. 2013 ^[71]	Bulgaria	HCC	Case report 67-years-old female	Intermittent administration of IL-2, BCG and oral melatonin	20 mg Daily	Immunomodulation
Bennukul et al. 2014 ^[59]	Thailand	HCC	In vitro Human HepG2 cell line	Melatonin	0.5–5 mM 24 and 48 h	Autophagy induction
Bennukul et al. 2014 ^[59]	Thailand	HCC	In vitro Human HepG2 cell line	Melatonin + Cisplatin	0.5–5 mM 24 and 48 h	Autophagy induction
Ordóñez et al. 2014 ^[15]	Spain	HCC	In vitro Human HepG2 cell line	Melatonin	1 mM 24 h	Angiogenesis and invasion inhibition
Ordóñez et al. 2014 ^[15]	Spain	HCC	In vitro Human HepG2 cell line	Melatonin + IL-1β	1 mM 24 h	Angiogenesis and invasion inhibition
Verma et al. 2014 ^[33]	Malaysia	HCC	In vivo Adult male mice Intraperitoneal injection of DEN (n = 6)	Intraperitoneal melatonin	0.5 mg/kg Thrice a week 10 weeks	Antioxidant activity Modulation of circadian rhythms
Laothong et al. 2015 ^[29]	Thailand	CCA	In vitro Human KKU-M055 and KKU-M214 cell lines	Melatonin	0.5, 1 and 2 mM 48 h	Oxidative stress activity Apoptosis induction
Moreira et al. 2015 ^[17]	Brazil	HCC	In vivo Male Wistar rats Intraperitoneal injection of DEN and 2-AAF administration at week 4 (n = 12)	Oral melatonin	1 mg/kg Daily 45 and 90 days	Apoptosis induction
Ordóñez et al. 2015 ^[16]	Spain	HCC	In vitro Human HepG2 cell line	Melatonin	2 mM 0.5–48 h	Apoptosis induction Autophagy induction
Colombo et al. 2016 ^[65]	Brazil	HCC	In vitro Human HepG2 cell line	Melatonin	1–10⁶ nM 24 h	Proliferation inhibition
Colombo et al. 2016 ^[65]	Brazil	HCC	In vitro Human HepG2 cell line	Melatonin	1 mM 24 h	Inhibition of hypoxia-derived invasion
Prieto-Domínguez et al. 2016 ^[18]	Spain	HCC	In vitro Human HepG2, HuH7 and Hep3B cell lines	Melatonin	0.1–2 mM	Proliferation inhibition Pro-oxidant activity Mitophagy induction Apoptosis induction
Prieto-Domínguez et al. 2016 ^[18]	Spain	HCC	In vitro Human HepG2, HuH7 and Hep3B cell lines	Melatonin + Sorafenib	0.1–2 mM
Bu et al. 2017 ^[48]	China	HCC	In vitro Human HepG2 cell line	Melatonin + Tunicamycin	10⁻⁶–1 mM	Apoptosis induction and ER stress
Cheng et al. 2017 ^[72]	China	HCC	In vitro Human HepG2 and Bel-7402 cell lines	Melatonin	0.1 mM	Immunomodulation
Cheng et al. 2017 ^[72]	China	HCC	In vivo 6-weeks-old female BALB/c nude mice Injected with Exo-con or Exo-MT (0.1 mM melatonin)	Exo-MT	100 µL Daily 10 days	Immunomodulation
Hao et al. 2017 ^[52]	China	HCC	In vitro Human Bel-7402, SNU-449, HepG2 and Hep3B 2.1-7 cell line	Melatonin	1 mM 48 h	Proliferation inhibition Inhibition of cell migration ability Apoptosis induction
Hao et al. 2017 ^[52]	China	HCC		Melatonin + CDDP	1 mM 48 h
Lin et al. 2017 ^[53]	China	HCC	In vitro Human HuH7 cell line	Melatonin	1–5 mM 48 h	Proliferation inhibition Apoptosis induction
Lin et al. 2017 ^[53]	China	HCC	In vitro Human HuH7 cell line	Melatonin + Sorafenib	1–5 mM 48 h	Proliferation inhibition Apoptosis induction
Liu et al. 2017 ^[60]	China	HCC	In vitro Human HepG2 and Bel-7402 cell lines	Melatonin	10 µM 48 h	Apoptosis induction
				Melatonin + Sorafenib	1–100 µM 48 h	Proliferation inhibition
				Melatonin + Sorafenib	10 µM 48 h	Apoptosis induction Autophagy blockage
Long et al. 2017 ^[37]	China	HCC	In vitro Human Bel-7402, SMMC-7721 HCC cell lines Human normal liver L02 cell line	Melatonin	0.2–2 mM 48–72 h	Proliferation inhibition
				Melatonin + Sorafenib	1 mM 48 h 2 weeks	Proliferation inhibition Cell cycle arrest
			In vivo 4-weeks-old female BALB/c nude mice Subcutaneous injection of SMMC-7721 cells (n = 4)	Intraperitoneal melatonin	25 mg/kg Daily 18 days	Tumor growth inhibition
				Intraperitoneal melatonin + sorafenib	25 mg/kg Daily 18 days	Tumor growth inhibition
Prieto-Domínguez et al. 2017 ^[4]	Spain	HCC	In vitro Human Hep3B cell line	Melatonin	1 or 2 mM 24 or 48 h	Pro-oxidant activity Proliferation inhibition
Prieto-Domínguez et al. 2017 ^[4]	Spain	HCC	In vitro Human Hep3B cell line	Melatonin + Sorafenib	1 or 2 mM 24 or 48 h	Proliferation inhibition Blockade of sorafenib-induced mitophagy
Sánchez et al. 2017 ^[38]	Spain	HCC	In vivo 6-weeks-old male ICR mice Intraperitoneal injection of DEN	Intraperitoneal melatonin	5 or 10 mg/kg Daily 10, 20, 30, 40 weeks	Cell cycle arrest Modulation of sphingolipid metabolism
Wang et al. 2017 ^[66]	Taiwan	HCC	In vitro Human HepG2 and HuH7 cell lines	Melatonin	1 mM 12, 24, 36, 48, 60 and 72 h	Proliferation inhibition
					1 mM 24, 48 and 72 h	Suppression of cell migration ability
					1 mM 24 h	EMT inhibition
			In vivo 6-to-8-weeks-old male BALB/c nude mice Subcutaneous injection of HuH7 cells (n = 10)	Intraperitoneal melatonin	40 mg/kg Five days per week	Tumor growth inhibition EMT suppression
Wongsena et al. 2017 ^[73]	Thailand	CCA	In vivo 6-to-8-weeks-old male Syrian golden hamsters Oral infection with 50 metacercariae of Opisthorchis viverrini and oral administration with DEN (n = 7)	Oral melatonin	50 mg/kg Daily 30 days	Immunomodulation
Chen et al. 2018 ^[68]	Taiwan	HCC	In vitro Human HuH7 and HepG2 cell lines	Melatonin	1 mM 12, 24, 36, 48, 60 and 72 h	Proliferation inhibition
				Melatonin	1 mM 24, 48 and 72 h	Suppression of migration and invasion abilities
				Melatonin + Etoposide	1 mM 12, 24, 36, 48, 60, and 72 h	Proliferation inhibition Apoptosis induction
				Melatonin + Camptothecin	1 mM 24 h	Proliferation inhibition Apoptosis induction
Chen et al. 2018 ^[68]	Taiwan	HCC	In vivo 6-weeks-old male BALB/c nude mice Subcutaneous injection of HuH7 cells (n = 6)	Intraperitoneal melatonin	40 mg/kg Five days/week 25 days	Tumor growth inhibition Apoptosis induction
Chen et al. 2018 ^[68]	Taiwan	HCC		Intraperitoneal melatonin + etoposide	40 mg/kg Five days/week 25 days	Tumor growth inhibition Apoptosis induction
Colombo et al. 2018 ^[46]	Brazil	HCC	In vitro Human HepG2 cell line	Melatonin	1 mM 24 h	Increase of NF-κB protein expression
Dauchy et al. 2018 ^[34]	USA	HCC	In vivo Male Buffalo rats Implantation of Morris 7288CTC hepatomas (control: n = 6; experimental: n = 9)	Endogenous melatonin	Increase of endogenous melatonin levels	Tumor growth inhibition
Sánchez et al. 2018 ^[14]	Spain	HCC	In vitro Human Hep3B cell line	Melatonin	0.5 or 1 mM 1 h	Proliferation inhibition Apoptosis induction
				Melatonin + SR9009	0.5 or 1 mM 1 h	Proliferation inhibition
				Melatonin + Bmal1 siRNA	0.5 or 1 mM 24 h	Proliferation inhibition Apoptosis induction
			In vivo 6-weeks-old male ICR mice Intraperitoneal injection of DEN (n = 4–8)	Intraperitoneal melatonin	5 or 10 mg/kg Daily 10, 20, 30, 40 weeks	Circadian clock modulation Cell cycle arrest Apoptosis induction
Wang et al. 2018 ^[69]	Taiwan	HCC	In vitro Human HepG2 and HuH7 cell lines	Melatonin	1 and 2 mM 12, 24, 36, 48, 60 and 72 h	Proliferation inhibition
				Melatonin	1 and 2 mM 24, 48 and 72 h	Suppression of migration and invasion abilities
				Melatonin + let-7i-3p inhibitor	1 and 2 mM 24 and 48 h	Proliferation inhibition Migration and invasion suppression
			In vivo 6–8-weeks-old male BALB/c nude mice Subcutaneous injection of HuH7 cells (n = 6)	Intraperitoneal melatonin	40 mg/kg 5 days per week 35 days	Tumor growth inhibition
El-Magd et al. 2019 ^[74]	Egypt	HCC	In vivo Adult female rats Intraperitoneal injection of DEN and oral administration of 2-AAF at week 2 (n = 10)	Intraperitoneal melatonin	20 mg/kg Twice a week 5 weeks	Apoptosis induction Antioxidant activity Reduction of angiogenesis and metastasis
				Intraperitoneal melatonin + MSCs	20 mg/kg Twice a week 5 weeks
				Intraperitoneal injection of MSCs preincubated with melatonin	5 µM 24 h
Mohamed et al. 2019 ^[75]	Egypt	HCC	In vivo Adult female rats Intraperitoneal injection of DEN followed by oral administration of 2-AAF at week 2 (n = 10)	Intraperitoneal melatonin	20 mg/kg Twice a week 5 weeks	Tumor growth inhibition Apoptosis induction
Mohamed et al. 2019 ^[75]	Egypt	HCC		Intraperitoneal injection of MSCs preincubated with melatonin 5 µM for 24 h		Tumor growth inhibition Apoptosis induction
Zhang et al. 2019 ^[39]	China	HCC	In vitro Human HepG2 cell line	Melatonin	3 mM 48 h	Suppression of migration
				Melatonin	1 mM 14 days	Proliferation inhibition
				Melatonin + EGCG	3 mM 48 h	Suppression of migration
				Melatonin + EGCG	1 mM 14 days	Proliferation inhibition
Zhou et al. 2019 ^[61]	China	HCC	In vitro Human HepG2, 7721 and HuH7 HCC cell lines Human liver L02 cell line	Melatonin	1–100 µM 48 h	Apoptosis induction
				Melatonin	10 µM 48 h	Autophagy inhibition
				Melatonin + Sorafenib	1–100 µM 48 h	Proliferation inhibition Apoptosis induction
				Melatonin + Sorafenib	10 µM 48 h	Autophagy inhibition
Ao et al. 2020 ^[54]	China	HCC	In vitro Human HepG2 and HuH7 cell lines	Melatonin	2.5 mM 24 h	Apoptosis induction
Mi and Kuang 2020 ^[40]	China	HCC	In vitro Human HepG2 and Hep3B cell lines	Melatonin	1 or 2 mM 24, 48, 72, 96 h	Proliferation inhibition
				Melatonin	1 or 2 mM 48 h	Cell cycle arrest
				Melatonin + Cisplatin	1 or 2 mM 24 and 48 h	Proliferation inhibition Apoptosis induction
Wang et al. 2020 ^[55]	China	HCC	In vitro Human SMMC-7721, cell line	Melatonin + Regorafenib	50 µM 24 h	Antioxidant activity Apoptosis induction

2-AAF, 2-acetylaminofluorene; AmB, amphotericin B; BCG, Bacillus Calmette-Guerin; Bmal1, brain and muscle arnt-like protein 1; CCA, cholangiocarcinoma; CDDP, Cis-dichlorodiamineplatinum; DEN, diethylnitrosamine; EGCG, (–)-epigallocatechin-3-gallate; EMT, epithelial-to-mesenchymal transition; ER, endoplasmic reticulum; Exo-con, exosomes from HepG2 cells; Exo-MT, exosomes from melatonin-treated HepG2 cells; HCC, hepatocarcinoma; MF, magnetic field; IL-1β, interleukin 1 beta; IL-2, interleukin-2; MSCs, mesenchymal stem cells; NF-κB, nuclear factor-kappa B; RNAi, interference RNA; siRNA, small interference RNA.

8. Conclusions

Melatonin has shown to exert antitumor effects in liver tumors, not only in the prevention but also in the treatment of the main primary liver tumors, HCC and CCA, by modulating a wide number of cellular processes, even protecting cells from the hepatotoxicity of other drugs. Among melatonin’s effects, as showed in Figure 1, it improves the immune response, enhances apoptosis, and positively influences the cell cycle and circadian rhythms; it also impairs tumor angiogenesis, invasion and cell proliferation. Considering its different roles on autophagy, melatonin may modulate this process depending on cellular context, always aimed at hindering tumor progression. Finally, combination studies with different molecule types, antitumor drugs, flavonoids and chemotherapeutics, provide evidence of the potential effects of melatonin as a coadjuvant agent to improve current treatments. Overall, research findings support a role for melatonin as a promising drug in the treatment armamentarium of liver tumors.

Figure 1. Cellular processes and protein expression modulated by melatonin in liver tumors. CAT, catalase; CDK, cyclin-dependent kinase; cIAP, cellular inhibitor apoptotic proteins; COX-2, cyclooxygenase-2; ERCC1, DNA excision repair cross complementary 1 protein; ERK, extracellular signal-regulated kinase; FOXA2, forkhead box A2; FoxO3a, forkhead box protein O3; foxp3, forkhead box P3; GPx, glutathione peroxidase; GSH, reduced glutathione; GST, glutathione S-transferase; HIF-1α, hypoxia-inducible factor 1α; IL-1, interleukin-1; IL-1β, interleukin 1 beta; IL-6, interleukin-6; IL-10, interleukin-10; iNOS, inducible nitric oxide synthase; JNK, c-Jun N-terminal kinase 1; LC3, microtubule-associated protein 1 light chain 3; lncRNA, long non-coding RNA; MEK, MAPK/ERK kinase 1; MMP-9, matrix metalloproteinase 9; Mn-SOD, manganese superoxide dismutase; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-kappa B; Nrf2, nuclear erythroid 2-related factor 2; PARP, poly(ADP-ribose) polymerase; PCNA, proliferating cell nuclear antigen; PD-L1, programmed death ligand 1; PINK1, PTEN induced putative kinase 1; RAF-1, ras activated factor 1; ROS, reactive oxygen species; Sirt3, sirtuin 3; Snail, zinc finger protein SNAI1; SOD, superoxide dismutase; TBARS, thiobarbituric acid reactive substances; TGF-β, transforming growth factor β; Th17, IL-17-producing T helper; TIMP-1, tissue inhibitor of metalloproteinases 1; TNF-α, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor; XIAP, cellular and X-linked inhibitor apoptotic proteins.

The entry is from 10.3390/antiox10010103

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Paula Fernández-Palanca

Carolina Méndez Blanco

Flavia Fondevila

María Tuñón

Jose L Mauriz

Javier González-Gallego

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