title: Identification of eusynstyelamide B as a potent cell cycle inhibitor following the generation and screening of an ascidian-derived extract library using a real time cell analyzer.
abstract: Ascidians are marine invertebrates that have been a source of numerous cytotoxic compounds. Of the first six marine-derived drugs that made anticancer clinical trials, three originated from ascidian specimens. In order to identify new anti-neoplastic compounds, an ascidian extract library (143 samples) was generated and screened in MDA-MB-231 breast cancer cells using a real-time cell analyzer (RTCA). This resulted in 143 time-dependent cell response profiles (TCRP), which are read-outs of changes to the growth rate, morphology, and adhesive characteristics of the cell culture. Twenty-one extracts affected the TCRP of MDA-MB-231 cells and were further investigated regarding toxicity and specificity, as well as their effects on cell morphology and cell cycle. The results of these studies were used to prioritize extracts for bioassay-guided fractionation, which led to the isolation of the previously identified marine natural product, eusynstyelamide B (1). This bis-indole alkaloid was shown to display an IC50 of 5 µM in MDA-MB-231 cells. Moreover, 1 caused a strong cell cycle arrest in G2/M and induced apoptosis after 72 h treatment, making this molecule an attractive candidate for further mechanism of action studies.
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Nathan, Qld 4111, Australia. michelle.liberio@griffithuni.edu.au.
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Liberio
authors.affiliation: Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Qld 4102, Australia. martin.sadowski@qut.edu.au.
authors.forename: Martin C
authors.initials: MC
authors.lastname: Sadowski
authors.affiliation: Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Qld 4102, Australia. colleen.nelson@qut.edu.au.
authors.forename: Colleen C
authors.initials: CC
authors.lastname: Nelson
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Nathan, Qld 4111, Australia. r.davis@griffith.edu.au.
authors.forename: Rohan A
authors.initials: RA
authors.lastname: Davis
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy; D002448:Cell Adhesion / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D014561:Urochordata / Q000737:chemistry*
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D007211:Indoles; C542026:eusynstyelamide B