title: Peloruside A enhances apoptosis in H-ras-transformed cells and is cytotoxic to proliferating T cells.
abstract: Peloruside A (peloruside), a compound isolated from the marine sponge Mycale hentscheli , inhibits growth of human (HL-60) and mouse (32D-ras) myeloid leukemic cells, as well as non-transformed 32D cells. Using the MTT cell proliferation assay and trypan blue dye exclusion tests, little difference was seen in growth inhibition between 32D and 32D- ras cells; however, peloruside was more cytotoxic to the oncogene-transformed cells. Peloruside also blocked 32D- ras cells more readily in G2/M of the cell cycle, leading to apoptosis. Annexin-V/propidium iodide staining of 32D and 32D- ras cells showed that 1.6 microM peloruside induced significant cell death by 36 hours in 32D cells (16% survival), but to comparable levels as early as 14 hours in 32D- ras cells (11% survival). There was no evidence for activation of either of the initiator caspases-8 or -9 by 0.1 microM peloruside following 12 hours of exposure. Peloruside inhibited T cell proliferation and IL-2 and IFN gamma production in both the mixed lymphocyte reaction and following CD3 cross-linking, and this effect was shown to be a non-specific cytotoxic effect. It is concluded that peloruside preferentially targets oncogene-transformed cells over non-transformed cells by inducing transformed cells to undergo apoptosis.
authors.affiliation: School of Biological Sciences, Victoria University of Wellington, PO Box 600, Wellington, New Zealand. john.h.miller@vuw.ac.nz
authors.forename: J H
authors.initials: JH
authors.lastname: Miller
authors.forename: B
authors.initials: B
authors.lastname: Rouwé
authors.forename: T N
authors.initials: TN
authors.lastname: Gaitanos
authors.forename: K A
authors.initials: KA
authors.lastname: Hood
authors.forename: K P
authors.initials: KP
authors.lastname: Crume
authors.forename: B T
authors.initials: BT
authors.lastname: Bäckström
authors.forename: A C
authors.initials: AC
authors.lastname: La Flamme
authors.forename: M V
authors.initials: MV
authors.lastname: Berridge
authors.forename: P T
authors.initials: PT
authors.lastname: Northcote
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D017252:CD3 Complex / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D011905:Genes, ras; D018922:HL-60 Cells; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors; D007376:Interleukin-2 / Q000037:antagonists & inhibitors; D007783:Lactones / Q000494:pharmacology*; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D013601:T-Lymphocytes / Q000187:drug effects*; D013997:Time Factors
chemical_list: D017304:Annexin A5; D019086:Bridged Bicyclo Compounds, Heterocyclic; D017252:CD3 Complex; D003432:Cross-Linking Reagents; D007376:Interleukin-2; D007783:Lactones; C414085:peloruside A; D007371:Interferon-gamma