title: Myristicin from nutmeg induces apoptosis via the mitochondrial pathway and down regulates genes of the DNA damage response pathways in human leukaemia K562 cells.
abstract: Myristicin, an allylbenzene, is a major active component of various spices, such as nutmeg and cinnamon, plants from the Umbelliferae family or in some essential oils, such as oils of clove or marjoram. Human exposure to myristicin is low but widespread due to consumption of these spices and essential oils, added to food (e.g. cola drinks) or in traditional medicine. Occasionally high dose exposure occurs, leading to various clinical symptoms, however the molecular mechanisms underlying them are unknown. Our previous studies revealed that myristicin is not genotoxic and yet presented apoptotic activity. Therefore, in this work we assessed the apoptotic mechanisms induced by myristicin in human leukaemia cells. In order to gain further insight on the potential of myristicin to modulate gene expression we also analysed alterations in expression of 84 genes associated with the DNA damage response pathway. The results obtained show that myristicin can induce apoptosis as characterised by alterations in the mitochondrial membrane potential, cytochrome c release, caspase-3 activation, PARP-cleavage and DNA fragmentation. The gene expression profile revealed an overall down regulation of DNA damage response genes after exposure to myristicin, with significant under-expression of genes associated with nucleotide excision repair (ERCC1), double strand break repair (RAD50, RAD51) and DNA damage signalling (ATM) and stress response (GADD45A, GADD45G). On the whole, we demonstrate that myristicin can alter mitochondrial membrane function, induce apoptosis and modulate gene expression in human leukaemia K562 cells. This study provides further detail on the molecular mechanisms underlying the biological activity of myristicin.
authors.affiliation: CIGMH - Department of Genetics, Faculty of Medical Sciences, Universidade Nova de Lisboa, Rua da Junqueira, 100, 1349-008 Lisboa, Portugal.
authors.forename: Célia
authors.initials: C
authors.lastname: Martins
authors.affiliation: CIGMH - Department of Genetics, Faculty of Medical Sciences, Universidade Nova de Lisboa, Rua da Junqueira, 100, 1349-008 Lisboa, Portugal.
authors.forename: Carolina
authors.initials: C
authors.lastname: Doran
authors.affiliation: CIGMH - Department of Genetics, Faculty of Medical Sciences, Universidade Nova de Lisboa, Rua da Junqueira, 100, 1349-008 Lisboa, Portugal.
authors.forename: Inês C
authors.initials: IC
authors.lastname: Silva
authors.affiliation: CIGMH - Department of Genetics, Faculty of Medical Sciences, Universidade Nova de Lisboa, Rua da Junqueira, 100, 1349-008 Lisboa, Portugal.
authors.forename: Claudia
authors.initials: C
authors.lastname: Miranda
authors.affiliation: CIGMH - Department of Genetics, Faculty of Medical Sciences, Universidade Nova de Lisboa, Rua da Junqueira, 100, 1349-008 Lisboa, Portugal.
authors.forename: José
authors.initials: J
authors.lastname: Rueff
authors.affiliation: CIGMH - Department of Genetics, Faculty of Medical Sciences, Universidade Nova de Lisboa, Rua da Junqueira, 100, 1349-008 Lisboa, Portugal. Electronic address: sebastiao.rodrigues@fcm.unl.pt.
authors.forename: António S
authors.initials: AS
authors.lastname: Rodrigues
mesh_terms: D000081248:Allylbenzene Derivatives; D017209:Apoptosis / Q000187:drug effects*; D001593:Benzyl Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004148:Dioxolanes / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D020014:K562 Cells; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D015394:Molecular Structure; D026323:Myristica / Q000737:chemistry*; D016133:Polymerase Chain Reaction; D011748:Pyrogallol / Q000031:analogs & derivatives* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D059467:Transcriptome
chemical_list: D000081248:Allylbenzene Derivatives; D001593:Benzyl Compounds; D004148:Dioxolanes; D011748:Pyrogallol; C005246:myristicin; D045304:Cytochromes c
keywords: Apoptosis; Gene expression; Leukaemia; Mitochondria; Myristicin