Photophysical studies on melatonin and its receptor agonists.
Previous work has demonstrated that melatonin inhibits the growth of both dermal and uveal melanoma cells. Recent clinical trials have found that melatonin is an efficacious treatment for metastatic dermal melanoma. The goal of this study was to provide further insight into the oncostatic mechanism(s) of melatonin. The inhibition of the growth of uveal melanoma cells is dose-dependent (0.1-10 nM) within the range of endogenous melatonin concentrations (2 nM) found in the human aqueous humor. We know that this inhibition of growth is receptor-mediated, at least in part, because uveal melanoma cell growth was also blocked by the agonists of melatonin receptors. There are two known membrane receptors for melatonin (Mel(1a) and Mel(1b)) and one known nuclear receptor (Mel2). To determine if singlet oxygen production and/or quenching contributed to the growth inhibition of melatonin, we examined the photophysical properties of melatonin and its agonists. Using flash photolysis, we determined that melatonin and its membrane receptor agonist 6-chloromelatonin (Mel(1a-b), Lilly, Indianapolis, IN) produced very little singlet oxygen (psidelta = 0.073 and psidelta = 0.01, respectively). There was no detectable singlet oxygen phosphorescence at 1,270 nm for the nuclear receptor agonist CG-52608 (Mel2, Novartis, Basel, Switzerland). In contrast, the agonist of the Mel(1b) receptor, S-20098 (Servier, Paris, France), produced singlet oxygen with a quantum efficiency of psidelta = 0.34. Singlet oxygen was quenched by melatonin and 6-chloromelatonin at approximately the same rate (6.1 x 10(7) M(-1)s(-1) and 6.0 x 10(7) M(-1)s(-1) in CD3OD), while the rate of quenching for the nuclear receptor agonist CG-52608 and membrane receptor agonist S-20098 was less (2.2 x 10(7) M(-1)s(-1) and 1.5 x 10(7) M(-1) s(-1), respectively). It appears that the production of singlet oxygen by melatonin would not be sufficient to directly block the proliferation of melanoma cells, but may activate gene products that could contribute to the oncostatic effect.
Roberts
J E
JE
Fordham University, New York, NY 10023, USA. jroberts@maryfordham.edu
Hu
D N
DN
Martinez
L
L
Chignell
C F
CF
D000081:Acetamides / Q000737:chemistry*; D006415:Hematoporphyrins / Q000737:chemistry; D007737:Kynurenine / Q000737:chemistry; D008163:Luminescent Measurements; D008550:Melatonin / Q000819:agonists / Q000031:analogs & derivatives* / Q000737:chemistry*; D010100:Oxygen / Q000737:chemistry; D043803:Phenalenes; D010777:Photochemistry; D011083:Polycyclic Compounds / Q000737:chemistry / Q000528:radiation effects; D011956:Receptors, Cell Surface / Q000819:agonists*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D044094:Receptors, Melatonin; D013056:Spectrophotometry, Ultraviolet; D013844:Thiazoles / Q000737:chemistry*; D013882:Thiosemicarbazones / Q000737:chemistry*; D014466:Ultraviolet Rays; D009281:Naphthalenes
D000081:Acetamides; D006415:Hematoporphyrins; D007737:Kynurenine; D008550:Melatonin; D010100:Oxygen; D043803:Phenalenes; D011083:Polycyclic Compounds; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D044094:Receptors, Melatonin; D013844:Thiazoles; D013882:Thiosemicarbazones; C084711:agomelatine; D009281:Naphthalenes; C038036:phenalen-1-one; C024100:6-chloromelatonin; C092451:CGP 52608