title: Melatonin inhibits cell proliferation and induces caspase activation and apoptosis in human malignant lymphoid cell lines.
abstract: Melatonin exerts strong anti-tumour activity via several mechanisms, including anti-proliferative and pro-apoptotic effects in addition to its potent antioxidant activity. Several studies have investigated the effects of melatonin on haematological malignancies. However, the previous studies investigating lymphoid malignancies have been largely restricted to a single type of malignancy, Burkitt's lymphoma (BL). Thus, we examined the actions of melatonin on the growth and apoptosis in a small panel of cell lines representing different human lymphoid malignancies including Ramos (Epstein-Barr virus-negative BL), SU-DHL-4 (diffuse large B cell lymphoma), DoHH2 (follicular B non-Hodgkin lymphoma) and JURKAT (acute T cell leukaemia). We showed that melatonin promotes cell cycle arrest and apoptosis in all these cells, although there was marked variations in responses among different cell lines (sensitivity; Ramos/DoHH2 > SU-DHL-4 > JURKAT). Melatonin-induced apoptosis was relatively rapid, with increased caspase 3 and PARP cleavage detected within 0.5-1 h following melatonin addition. Moreover, there was evidence for rapid processing of both caspase 9, as well as a breakdown of the mitochondrial inner transmembrane potential. On the contrary, caspase activation was detected only in SU-DHL-4 and Ramos cells following melatonin treatment suggesting that the extrinsic pathway does not make a consistent contribution to melatonin-induced apoptosis in malignant lymphocytes. Although all cell lines expressed the high-affinity melatonin receptors, MT1 and MT2, melatonin-induced caspase activation appeared to be independent these receptors. Our findings confirm that melatonin could be a potential chemotherapeutic/preventive agent for malignant lymphocytes. However, it is necessary to take into account that different lymphoid malignancies may differ in their response to melatonin.
authors.affiliation: Faculty of Medicine, Cancer Research UK Centre, Cancer Sciences, Southampton General Hospital, University of Southampton, Southampton, UK. hidalgosanz@us.es
authors.forename: Marina
authors.initials: M
authors.lastname: Sánchez-Hidalgo
authors.forename: Melanie
authors.initials: M
authors.lastname: Lee
authors.forename: Catalina A
authors.initials: CA
authors.lastname: de la Lastra
authors.forename: Juan M
authors.initials: JM
authors.lastname: Guerrero
authors.forename: Graham
authors.initials: G
authors.lastname: Packham
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D008228:Lymphoma, Non-Hodgkin / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D008550:Melatonin / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D044122:Receptor, Melatonin, MT1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D044123:Receptor, Melatonin, MT2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D008550:Melatonin