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| Chemotherapy agents | Experimental studies | Drugs and doses | Administration route | Outcomes | Underlying mechanisms | References |
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| Anthracyclines | NIH3T3 cells | DOX (2.6 μM for 24 h) + melatonin (1 μM for 24 h) | | Countered apoptosis generated by DOX alone | AMPK-Ppar gamma-dependent mechanisms | [94] |
| Male Wistar-Albino rats | DOX (18 mg/kg) + melatonin (10 mg/kg/day, 7 days) | Intraperitoneal | Protected the heart against DOX-induced cardiotoxicity | Melatonin treatment prevented the elevation of the ST segment and R amplitude, as well as the elevation of cardiac injury markers and lipid peroxidation, and it prevented the decrease of antioxidant enzyme activity | [84] |
| Male Sprague-Dawley rats | DOX (10 mg/kg) + melatonin (15 mg/kg) | Intraperitoneal | Melatonin controlled oxidative stress and modulated iron, ferritin, and transferrin levels | Ameliorated oxidative stress by controlling iron and binding protein levels | [85] |
| Buffalo strain rats | DOX (2.5 mg/kg) + melatonin (20 mg/kg) | Intraperitoneal | Melatonin stimulated the activity of protective antioxidative enzymes in myocardial cells of rats | Melatonin increased GSH levels and stimulated CAT activity | [86] |
| Sprague-Dawley rats | DOX (15 mg/kg) + melatonin (84 mg/kg) | Intraperitoneal | Melatonin maintained the plasma zinc levels | Zinc accumulation protects against oxidative stress and melatonin inhibited the DOX-induced decrease in plasma zinc levels | [87] |
| Male Wistar rats | DOX (7.5 mg/kg) + melatonin (6.0 mg/kg) | Intraperitoneal | Melatonin prevented DOX-induced lipid peroxidation in rat liver | Melatonin-induced gene expression changes | [87] |
| Male Wistar rats | Melatonin (90 mg/kg) | Intraperitoneal | Cardiac function was improved and lipid peroxidation was decreased | Melatonin provides protection against DOX toxicity via an attenuation of lipid peroxidation | [88] |
| Ehrlich ascite carcinoma-bearing mice | DOX (4 mg/kg/week, 2 weeks) + melatonin (5 mg/kg/day, 15 days) | Intraperitoneal | Melatonin protected against cardiotoxicity and enhanced its antitumor activity to a more significant extent than did vitamin E | The cardiac contents of total protein, GSH, and SOD were increased, while the cardiac content of MDA was decreased | [98] |
| Male Wistar rats | Epirubicin (10 mg/kg) + melatonin (200 mg/kg) | Intraperitoneal | Melatonin protected against cardiotoxicity induced by epirubicin | Melatonin was partially attributed to the suppression of epirubicin-induced nitrozative stress | [101] |
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| Alkylating agents | HBE cells | Yperite or with MEC + melatonin (100 μM) | | Melatonin prevented mustard-induced anoikis | Inhibition of caspase-dependent mitochondrial permeability transition | [120] |
| NMRI mice | CP (200 mg/kg) + melatonin at different concentrations (2.5, 5, 10, and 20 mg/kg) | Intraperitoneal | Melatonin prevented CP-induced oxidative toxicity in mouse lung tissues | The activities of the antioxidant defense system, ROS scavenging, and free radical quenching were increased | [106] |
| Female Wistar rats | CP (75 mg/kg) + melatonin (5 mg/kg) | Intraperitoneal | Melatonin significantly improved bladder symptoms and histological damage due to CP-induced cystitis | Diminishing bladder oxidative stress, blocking iNOS and peroxynitrite production, upregulating HO-1, and downregulating the expression of SP | [107] |
| Male Sprague-Dawley rats | CP (150 mg/kg) + melatonin (10 mg/kg) | Intraperitoneal | Melatonin treatment reduced bladder damage and apoptosis | Upregulating Nrf2 and nuclear transcription factor NF-κB expression | [109] |
| Male ICR mice | CP (150 mg/kg) + melatonin (10 mg/kg) | Intraperitoneal | Melatonin cotreatment prevented the development of hyperplastic urothelium | Decreasing proliferation and apoptotic indices and causing the higher differentiation state of superficial urothelial cells | [110] |
| Male Wistar albino rats | CP (100 mg/kg) + melatonin (10 mg/kg) | Intraperitoneal | Melatonin may reduce CP-induced testicular damage | The antioxidative properties of indoleamine existed in the chemical structure | [111] |
| NMRI mice | CP (60 mg/kg) + melatonin (2.5, 5, 10, and 20 mg/kg) | Intraperitoneal | Melatonin has potent antigenotoxic effects and suppression of chromosome aberrations | Scavenging of free radicals and increased antioxidant status | [112] |
| Albino Wistar rats | CP (75 mg/kg) + melatonin (40 or 100 mg/kg) | Intraperitoneal | Melatonin resulted in global ANS activity elevation, with a marked sympathetic tone predominance | Melatonin modulates autonomic activity via nonreceptor mechanisms | [114] |
| Male Wistar rats | HN2 (0.5 mg/kg) + melatonin (20 mg/kg or 40 mg/kg) | Intraperitoneal | Melatonin reduced mustard-induced toxicity in the lungs | Melatonin restored oxidative and nitrosative stress markers in a dose-dependent manner | [117] |
| Male Sprague-Dawley rats | MEC (3.5 mg/kg) + melatonin (100 mg/kg) | MEC via transdermal route and melatonin via intraperitoneal route | Melatonin has anti-inflammatory properties, as well as antioxidant properties | These increases and elevated NOx levels were ameliorated | [196] |
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| Platinum | Hepatocellular carcinoma HepG2 cells | Melatonin (1 mM) + cisplatin (20 μM) | | Melatonin attenuated cisplatin-induced HepG2 cell death | Regulation of mTOR and ERCC1 expressions | [130] |
| SK-LU-1 cell line | Cisplatin (11 and 4 μM) + melatonin (1 or 2 mM) | | Melatonin enhanced cisplatin-induced cytotoxicity and apoptosis | Elevating mitochondrial membrane depolarization, activating caspases-3/7, and inducing cell cycle arrest in the S phase | [132] |
| SH-SY5Y cells | Melatonin (10 μM, 50 μM) + Oxa (100 μM) | | Melatonin protects against the oxaliplatin-induced pain and neuropathic deficits | Preventing the loss of mitochondrial membrane potential (Ψm), inhibiting Bcl-2/Bax ratio and releasing sequestered cytochrome c, and promoting neuritogenesis | [136] |
| HT-29 cells | Oxa (0-50 μM) + melatonin (15 and 30 μM) | | Melatonin improved mitochondrial electron transport chain function and maintained cellular bioenergetics by improving the ATP levels | Ameliorating nitrooxidative stress and preventing nitrosylation of proteins and loss of antioxidant enzymes | [135] |
| SH-SY5Y cells | Oxa (10 μM, 50 μM, and 100 μM) + melatonin (10 μM) | | Melatonin attenuated oxaliplatin-induced apoptosis | Inhibition of GSH depletion and Mcl-1 downregulation | [136] |
| Male Sprague Dawley rats | Cisplatin (7 mg/kg) + melatonin (5 mg/kg) | Intraperitoneal | Melatonin markedly reduced renal cytotoxicity and DNA fragmentation | Scavenge hydroxyl radical (•OH) directly | [123] |
| Male Wistar rats | Melatonin (4 mg/kg, 10 days) + cisplatin (7 mg/kg) | Intraperitoneal | Melatonin suppressed cisplatin-induced nephrotoxicity | Increasing Nrf2 accumulation in the nuclear fraction and increasing the expression of HO-1 | [122] |
| Female Swiss mice | Melatonin (5, 10, or 20 mg/kg) + cisplatin (5 mg/kg) | Intraperitoneal | Melatonin effectively protected the ovaries against cisplatin-induced damage | The MT1 receptor and melatonin antioxidant effects | [125] |
| Female CD-1 mice | Cisplatin (2 mg/kg) + melatonin (15 or 30 mg/kg) | Intraperitoneal | Melatonin attenuated cisplatin-induced follicle loss | Preventing the phosphorylation of PTEN/AKT/FOXO3a pathway | [126] |
| Wistar rats | Melatonin (10 mg/kg) + Oxa (4 mg/kg) | Intraperitoneal | Melatonin ameliorated the mitochondrial lipid peroxidation levels and protein carbonyl content | Modulating altered nonenzymatic and enzymatic antioxidants and complex enzymes of mitochondria | [54] |
| Male Sprague-Dawley rats | Melatonin (20 mg/kg + Oxa 5 mg/kg) | Intraperitoneal | Melatonin had anti-inflammatory and antiallodynia effects | Melatonin inhibited synthesis of inflammatory mediators | [138] |
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| Antimetabolite | Male Wistar rats | Melatonin (20 and 40 mg/kg) + MTX (7 mg/kg) | Intraperitoneal | Melatonin reduced small intestinal damage and ameliorates MTX-induced enteritis | Attenuating oxidative stress and restoring the activities of the antioxidant enzymes | [141] |
| Male Wistar rats | Melatonin (20 and 40 mg/kg) + MTX (7 mg/kg) | Intraperitoneal | Melatonin protected against MTX-induced small intestinal damage | Attenuation of nitrosative stress, protein tyrosine nitration, and PARP activation | [142] |
| Male Wistar rats | MTX (7 mg/kg) + melatonin (40 mg/kg) | Intraperitoneal | Melatonin reduced renal damage via antioxidant and anti-inflammatory activities | Reduction of oxidative stress and alteration in the activity of antioxidant enzymes, as well as elevation in myeloperoxidase activity | [143] |
| Male Sprague Dawley rats | MTX (13.4 mg/kg) + melatonin (10 mg/kg) | Intraperitoneal | Melatonin prevented MTX-induced hepatotoxicity | Through their antioxidant- and radical-scavenging activities | [145] |
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| Mitotic inhibitors | Sprague Dawley rats, the 50B11 immortalized DRG neuronal stem cell line | Paclitaxel (100 μM) + melatonin (1 μM) | Intraperitoneal | Melatonin protected against neuropathic pain and limits paclitaxel-induced mitochondrial dysfunction in vitro | Limiting the development of mechanical hypersensitivity | [153] |
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| Molecular-targeted agents | Male Sprague-Dawley rats | Trastuzumab (10 mg/kg) + melatonin (10 mg/kg, 2 days) | Intraperitoneal | Melatonin was effective in preventing trastuzumab-induced cardiotoxicity | Reversing oxidative stress markers | [156] |
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