title: Antiproliferative and pro-apoptotic activity of eugenol-related biphenyls on malignant melanoma cells.
abstract: BACKGROUND
  Malignant melanoma is one of the most aggressive skin cancer and chemotherapeutic agents currently in use are still unsatisfactory. Prevention and early diagnosis are the only effective tools against this tumour whose incidence and mortality rates are highly increased during the last decades in fair skin populations. Therefore the search for novel therapeutic approaches is warranted. Aim of this work was to identify and test new compounds with antiproliferative and cytotoxic activity on melanoma cells. We tested eugenol together with six natural and synthetic eugenol-related compounds for their capability to inhibit cell growth on primary melanoma cell lines established from patients' tissue samples.
  
  
  RESULTS
  Eugenol and isoeugenol monomers and their respective O-methylated forms did not show to inhibit melanoma cells proliferation. Conversely, the dimeric forms (biphenyls) showed some antiproliferative activity which was mild for dehydrodieugenol, higher for its O,O'-methylated form (O,O'-dimethyl-dehydrodieugenol), and markedly pronounced for the racemic mixture of the brominated biphenyl (6,6'-dibromo-dehydrodieugenol) (S7), being its enantiomeric form (S) the most effective compared to the other compounds. Such activity resulted to be selective against tumour cells, without affecting cultured normal human skin fibroblasts. Dose and time dependence curves have been obtained for the enantiomeric form S7-(S). Then IC50 and minimal effective doses and times have been established for the melanoma cell lines tested. TUNEL and phosphatidylserine exposure assays demonstrated the occurrence of apoptotic events associated with the antiproliferative activity of S7-(S). Cytotoxic activity and apoptosis induced by treating melanoma cells with eugenol-related biphenyls was partially dependent by caspase activation.
  
  
  CONCLUSIONS
  Our findings demonstrate that the eugenol related biphenyl (S)-6,6'-dibromo-dehydrodieugenol elicits specific antiproliferative activity on neuroectodermal tumour cells partially triggering apoptosis and its activity should be further investigated on in vivo melanoma models in order to evaluate the real anticancer effectiveness on such tumour.
authors.affiliation: Bio-molecular Chemistry Institute, National Research Council, Sassari, Italy. marina.pisano@icb.cnr.it
authors.forename: Marina
authors.initials: M
authors.lastname: Pisano
authors.forename: Gabriella
authors.initials: G
authors.lastname: Pagnan
authors.forename: Monica
authors.initials: M
authors.lastname: Loi
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Mura
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Tilocca
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Palmieri
authors.forename: Davide
authors.initials: D
authors.lastname: Fabbri
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Dettori
authors.forename: Giovanna
authors.initials: G
authors.lastname: Delogu
authors.forename: Mirco
authors.initials: M
authors.lastname: Ponzoni
authors.forename: Carla
authors.initials: C
authors.lastname: Rozzo
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001713:Biphenyl Compounds / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019281:Dimerization; D005054:Eugenol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D020128:Inhibitory Concentration 50; D008545:Melanoma / Q000188:drug therapy*; D012878:Skin Neoplasms / Q000188:drug therapy*; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D005054:Eugenol; C010574:biphenyl