The antiproliferative activity of melatonin in B65 rat dopaminergic neuroblastoma cells is related to the downregulation of cell cycle-related genes.
A potential application of melatonin is its ability to rescue many cell types from cell death, because of its antioxidant properties. Likewise, recent studies suggest that melatonin may also be used as an anti-tumor drug, due to its anti-proliferative properties in tumor cells when administered at physiologic or pharmacologic doses. In the present study, we investigated the mechanisms involved in the apoptosis induced by acute exposure to melatonin and roscovitine in the rat dopaminergic neuroblastoma B65 cell line. Cell growth studies revealed that, at 24 hr of treatment, roscovitine blocked cell growth and induced apoptosis whereas melatonin delayed cell growth and induced a slight increase in the number of apoptotic nuclei. Melatonin also increased the percentage of cells in the G1-phase of the cell cycle, whereas roscovitine blocked cells in the G2/M-phase. Both compounds significantly downregulated the transcriptional activity of cdk4, while melatonin also downregulated cdk2 and cyclin D1. Taken together, our data show that melatonin at millimolar concentrations inhibits dopaminergic B65 proliferation, induces cell apoptosis, and modulates cell cycle progression by inhibiting the transcriptional activity of cyclins and cdks related to the progression of the G1-phase.
Pizarro
Javier G
JG
Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, Barcelona, Spain.
Yeste-Velasco
Marc
M
Esparza
José Luis
JL
Verdaguer
Ester
E
Pallàs
Mercè
M
Camins
Antoni
A
Folch
Jaume
J
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004298:Dopamine / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology*; D008550:Melatonin / Q000627:therapeutic use*; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology*; D011687:Purines / Q000494:pharmacology; D051381:Rats; D000077546:Roscovitine; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D011687:Purines; D000077546:Roscovitine; D008550:Melatonin; D004298:Dopamine