title: Rapid and transient stimulation of intracellular reactive oxygen species by melatonin in normal and tumor leukocytes.
abstract: Melatonin is a modified tryptophan with potent biological activity, exerted by stimulation of specific plasma membrane (MT1/MT2) receptors, by lower affinity intracellular enzymatic targets (quinone reductase, calmodulin), or through its strong anti-oxidant ability. Scattered studies also report a perplexing pro-oxidant activity, showing that melatonin is able to stimulate production of intracellular reactive oxygen species (ROS). Here we show that on U937 human monocytes melatonin promotes intracellular ROS in a fast (<1 min) and transient (up to 5-6 h) way. Melatonin equally elicits its pro-radical effect on a set of normal or tumor leukocytes; intriguingly, ROS production does not lead to oxidative stress, as shown by absence of protein carbonylation, maintenance of free thiols, preservation of viability and regular proliferation rate. ROS production is independent from MT1/MT2 receptor interaction, since a) requires micromolar (as opposed to nanomolar) doses of melatonin; b) is not contrasted by the specific MT1/MT2 antagonist luzindole; c) is not mimicked by a set of MT1/MT2 high affinity melatonin analogues. Instead, chlorpromazine, the calmodulin inhibitor shown to prevent melatonin-calmodulin interaction, also prevents melatonin pro-radical effect, suggesting that the low affinity binding to calmodulin (in the micromolar range) may promote ROS production.
authors.affiliation: Dipartimento di Biologia, Universita' di Roma Tor Vergata, Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Radogna
authors.forename: Laura
authors.initials: L
authors.lastname: Paternoster
authors.forename: Milena
authors.initials: M
authors.lastname: De Nicola
authors.forename: Claudia
authors.initials: C
authors.lastname: Cerella
authors.forename: Sergio
authors.initials: S
authors.lastname: Ammendola
authors.forename: Annalida
authors.initials: A
authors.lastname: Bedini
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tarzia
authors.forename: Katia
authors.initials: K
authors.lastname: Aquilano
authors.forename: Maria
authors.initials: M
authors.lastname: Ciriolo
authors.forename: Lina
authors.initials: L
authors.lastname: Ghibelli
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002147:Calmodulin / Q000378:metabolism; D018929:Cell Culture Techniques; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism; D008550:Melatonin / Q000494:pharmacology*; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism*; D044122:Receptor, Melatonin, MT1 / Q000378:metabolism; D044123:Receptor, Melatonin, MT2 / Q000378:metabolism; D013997:Time Factors; D020298:U937 Cells
chemical_list: D002147:Calmodulin; D017382:Reactive Oxygen Species; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D005978:Glutathione; D008550:Melatonin