Microtubule-stabilizing properties of the avocado-derived toxins (+)-(R)-persin and (+)-(R)-tetrahydropersin in cancer cells and activity of related synthetic analogs.

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dc.contributor.author Field, Jessica J en
dc.contributor.author Kanakkanthara, Arun en
dc.contributor.author Brooke, Darby G en
dc.contributor.author Sinha, Saptarshi en
dc.contributor.author Pillai, Sushila D en
dc.contributor.author Denny, William en
dc.contributor.author Butt, Alison J en
dc.contributor.author Miller, John H en
dc.date.accessioned 2018-10-16T23:18:01Z en
dc.date.issued 2016-06 en
dc.identifier.issn 0167-6997 en
dc.identifier.uri http://hdl.handle.net/2292/42225 en
dc.description.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. en
dc.format.medium Print-Electronic en
dc.language eng en
dc.relation.ispartofseries Investigational new drugs en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights.uri https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm en
dc.subject Cell Line, Tumor en
dc.subject Microtubules en
dc.subject Humans en
dc.subject Persea en
dc.subject Ovarian Neoplasms en
dc.subject Fatty Alcohols en
dc.subject Acetates en
dc.subject Nitrobenzoates en
dc.subject Antineoplastic Agents, Phytogenic en
dc.subject Cell Cycle en
dc.subject Cell Proliferation en
dc.subject Binding Sites en
dc.subject Binding, Competitive en
dc.subject Drug Synergism en
dc.subject Female en
dc.subject M Phase Cell Cycle Checkpoints en
dc.subject G2 Phase Cell Cycle Checkpoints en
dc.subject ATP-Binding Cassette, Sub-Family B, Member 1 en
dc.title Microtubule-stabilizing properties of the avocado-derived toxins (+)-(R)-persin and (+)-(R)-tetrahydropersin in cancer cells and activity of related synthetic analogs. en
dc.type Journal Article en
dc.identifier.doi 10.1007/s10637-016-0341-z en
pubs.issue 3 en
pubs.begin-page 277 en
pubs.volume 34 en
dc.rights.holder Copyright: The author en
dc.identifier.pmid 26968704 en
pubs.end-page 289 en
pubs.publication-status Published en
dc.rights.accessrights http://purl.org/eprint/accessRights/RestrictedAccess en
pubs.subtype Research Support, Non-U.S. Gov't en
pubs.subtype Journal Article en
pubs.elements-id 525016 en
pubs.org-id Medical and Health Sciences en
pubs.org-id Medical Sciences en
pubs.org-id Auckland Cancer Research en
pubs.org-id Science en
pubs.org-id Science Research en
pubs.org-id Maurice Wilkins Centre (2010-2014) en
dc.identifier.eissn 1573-0646 en
pubs.record-created-at-source-date 2016-03-13 en
pubs.dimensions-id 26968704 en


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