title: The marine cytotoxin portimine is a potent and selective inducer of apoptosis.
abstract: Portimine is a recently discovered member of a class of marine micro-algal toxins called cyclic imines. In dramatic contrast to related compounds in this toxin class, portimine has very low acute toxicity to mice but is highly cytotoxic to cultured cells. In this study we show that portimine kills human Jurkat T-lymphoma cells and mouse embryonic fibroblasts (MEFs), with LC50values of 6 and 2.5 nM respectively. Treated cells displayed rapid caspase activation and phosphatidylserine exposure, indicative of apoptotic cell death. Jurkat cells overexpressing the anti-apoptotic protein Bcl-2 or Bax/Bak knockout MEFs were completely protected from portimine. This protection was apparent even at high concentrations of portimine, with no evidence of necrotic cell death, indicating that portimine is a selective chemical inducer of apoptosis. Treatment of the Bcl-2-overexpressing cells with both portimine and the Bcl-2 inhibitor ABT-737 proved a powerful combination, causing >90 % death. We conclude that portimine is one of the most potent naturally derived inducers of apoptosis to be discovered, and it displays strong selectivity for the induction of apoptotic pathways.
authors.affiliation: Department of Pathology, Centre for Free Radical Research, University of Otago Christchurch, PO Box 4345, Christchurch, New Zealand.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Cuddihy
authors.affiliation: Department of Pathology, Centre for Free Radical Research, University of Otago Christchurch, PO Box 4345, Christchurch, New Zealand.
authors.forename: Sarah
authors.initials: S
authors.lastname: Drake
authors.affiliation: Cawthron Institute, Private Bag 2, Nelson, New Zealand.
authors.forename: D Tim
authors.initials: DT
authors.lastname: Harwood
authors.affiliation: Cawthron Institute, Private Bag 2, Nelson, New Zealand.
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Selwood
authors.affiliation: Cawthron Institute, Private Bag 2, Nelson, New Zealand.
authors.forename: Paul S
authors.initials: PS
authors.lastname: McNabb
authors.affiliation: Department of Pathology, Centre for Free Radical Research, University of Otago Christchurch, PO Box 4345, Christchurch, New Zealand. mark.hampton@otago.ac.nz.
authors.forename: Mark B
authors.identifier: 0000-0002-7349-3729
authors.initials: MB
authors.lastname: Hampton
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D003603:Cytotoxins / Q000737:chemistry / Q000633:toxicity*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007097:Imines / Q000737:chemistry / Q000633:toxicity*; D019169:Jurkat Cells; D008387:Marine Toxins / Q000737:chemistry / Q000633:toxicity*; D051379:Mice; D015394:Molecular Structure
chemical_list: D051017:Apoptosis Regulatory Proteins; D003603:Cytotoxins; D007097:Imines; D008387:Marine Toxins
keywords: Caspase; Cell death; Cyclic imine; Natural product; Necrosis; Phosphatidylserine exposure