title: Microtubule-stabilizing properties of the avocado-derived toxins (+)-(R)-persin and (+)-(R)-tetrahydropersin in cancer cells and activity of related synthetic analogs.
abstract: The avocado toxin (+)-R-persin (persin) is active at low micromolar concentrations against breast cancer cells and synergizes with the estrogen receptor modulator 4-hydroxytamoxifen. Previous studies in the estrogen receptor-positive breast cancer cell line MCF-7 indicate that persin acts as a microtubule-stabilizing agent. In the present study, we further characterize the properties of persin and several new synthetic analogues in human ovarian cancer cells. Persin and tetrahydropersin cause G2M cell cycle arrest and increase intracellular microtubule polymerization. One analog (4-nitrophenyl)-deshydroxypersin prevents cell proliferation and blocks cells in G1 of the cell cycle rather than G2M, suggesting an additional mode of action of these compounds independent of microtubules. Persin can synergize with other microtubule-stabilizing agents, and is active against cancer cells that overexpress the P-glycoprotein drug efflux pump. Evidence from Flutax-1 competition experiments suggests that while the persin binding site on β-tubulin overlaps the classical taxoid site where paclitaxel and epothilone bind, persin retains activity in cell lines with single amino acid mutations that affect these other taxoid site ligands. This implies the existence of a unique binding location for persin at the taxoid site.
authors.affiliation: Centre for Biodiscovery, School of Biological Sciences, Victoria University of Wellington, PO Box 600, Wellington, 6140, New Zealand.|Seattle Genetics, Bothell, WA, 98021, USA.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Field
authors.affiliation: Centre for Biodiscovery, School of Biological Sciences, Victoria University of Wellington, PO Box 600, Wellington, 6140, New Zealand.|Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, 55905, USA.
authors.forename: Arun
authors.initials: A
authors.lastname: Kanakkanthara
authors.affiliation: Cawthron Institute, Private Bag 2, Nelson, New Zealand.|Auckland Cancer Society Research Centre, The University of Auckland, Auckland, New Zealand.
authors.forename: Darby G
authors.initials: DG
authors.lastname: Brooke
authors.affiliation: Centre for Biodiscovery, School of Biological Sciences, Victoria University of Wellington, PO Box 600, Wellington, 6140, New Zealand.
authors.forename: Saptarshi
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Centre for Biodiscovery, School of Biological Sciences, Victoria University of Wellington, PO Box 600, Wellington, 6140, New Zealand.
authors.forename: Sushila D
authors.initials: SD
authors.lastname: Pillai
authors.affiliation: Auckland Cancer Society Research Centre, The University of Auckland, Auckland, New Zealand.|Maurice Wilkins Centre, University of Auckland, Auckland, New Zealand.
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
authors.affiliation: Cancer Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Darlinghurst, New South Wales, Australia.
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Butt
authors.affiliation: Centre for Biodiscovery, School of Biological Sciences, Victoria University of Wellington, PO Box 600, Wellington, 6140, New Zealand. john.h.miller@vuw.ac.nz.
authors.forename: John H
authors.initials: JH
authors.lastname: Miller
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000085:Acetates / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D001667:Binding, Competitive; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D005233:Fatty Alcohols / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D008870:Microtubules / Q000378:metabolism; D009579:Nitrobenzoates / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D027421:Persea / Q000737:chemistry
chemical_list: C000625522:(4-nitrophenyl)deshydroxypersin; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000085:Acetates; D000972:Antineoplastic Agents, Phytogenic; D005233:Fatty Alcohols; D009579:Nitrobenzoates; C000625521:tetrahydropersin; C098164:persin
keywords: Cancer; Flutax-1; Microtubule-stabilizing agent; Multidrug resistance; Peloruside; Persin; Synergy; Taxoid binding site; Tetrahydropersin