title: Synergistic Cytotoxicity of Melatonin and New-generation Anticancer Drugs Against Leukemia Lymphocytes But Not Normal Lymphocytes.
abstract: The present study demonstrates specific sensitization of leukemia lymphocytes towards anticancer drugs using melatonin and clarifies the role of reactive oxygen species (ROS) for induction of apoptosis. The study covers four conventional and 11 new-generation anticancer drugs. Four parameters were analyzed simultaneously in leukemia and normal lymphocytes treated with drug, melatonin, or their combination: cell viability, induction of apoptosis, level of reactive oxygen species (ROS), and level of protein-carbonyl products. Almost all investigated combinations of melatonin with new-generation anticancer drugs were characterized by synergistic cytotoxicity towards leukemia lymphocytes, while the combinations with conventional drugs exhibited additive or antagonistic effects on cell viability. In leukemia lymphocytes, the additive cytotoxicity of doxorubicin plus melatonin was accompanied by low levels of ROS and protein-carbonyl products, as well as by suppression of apoptosis. In normal lymphocytes, none of the studied parameters changed significantly compared to cells treated with doxorubicin only. The combinations of everolimus plus melatonin and barasertib plus melatonin exhibited impressive synergistic cytotoxic effects on leukemia lymphocytes but did not affect the viability of normal lymphocytes. In leukemia cells, the synergistic cytotoxicity was accompanied by strong induction of apoptosis but a decrease of ROS to a level below that of the control. In normal lymphocytes, these combinations did not affect the level of ROS nor of protein-carbonyl products, and did not induce apoptosis. The data suggest that melatonin is a promising supplementary component in chemotherapy which allows the therapeutic doses of anticancer drugs to be reduced, minimizing their side-effects.
authors.affiliation: Medical Faculty, Trakia University, Stara Zagora, Bulgaria.|Institute of Biophysics & Biomedical Engineering, Bulgarian Academy of Sciences, Sofia, Bulgaria.
authors.forename: Zhivko
authors.initials: Z
authors.lastname: Zhelev
authors.affiliation: Medical Faculty, Trakia University, Stara Zagora, Bulgaria.
authors.forename: Donika
authors.initials: D
authors.lastname: Ivanova
authors.affiliation: Department of Molecular Imaging and Theranostics, National Institute of Radiological Sciences, National Institute for Quantum and Radiological Science and Technology, Chiba, Japan bakalova.rumiana@qst.go.jp.|Medical Faculty, Sofia University St. Kliment Ohridski, Sofia, Bulgaria.
authors.forename: Rumiana
authors.initials: R
authors.lastname: Bakalova
authors.affiliation: Department of Molecular Imaging and Theranostics, National Institute of Radiological Sciences, National Institute for Quantum and Radiological Science and Technology, Chiba, Japan.
authors.forename: Ichio
authors.initials: I
authors.lastname: Aoki
authors.affiliation: Department of Molecular Imaging and Theranostics, National Institute of Radiological Sciences, National Institute for Quantum and Radiological Science and Technology, Chiba, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Higashi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D019169:Jurkat Cells; D015458:Leukemia, T-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008550:Melatonin / Q000494:pharmacology* / Q000633:toxicity; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D050050:Protein Carbonylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D008550:Melatonin
keywords: Melatonin; anticancer drugs; apoptosis; leukemia lymphocytes; normal lymphocytes; reactive oxygen species