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

Jessica J. Field, Arun Kanakkanthara, Darby G. Brooke, Saptarshi Sinha, Sushila D. Pillai, William A. Denny, Alison J. Butt, John H. Miller

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)277-289
Number of pages13
JournalInvestigational New Drugs
Volume34
Issue number3
DOIs
StatePublished - Jun 1 2016

Fingerprint

Persea
Microtubules
Taxoids
Neoplasms
Excipients
Epothilones
Breast Neoplasms
persin
Cell Line
Estrogen Receptor Modulators
P-Glycoprotein
Tubulin
Paclitaxel
Cell Cycle Checkpoints
Polymerization
Estrogen Receptors
Ovarian Neoplasms
Cell Cycle
Binding Sites
Cell Proliferation

Keywords

  • Cancer
  • Flutax-1
  • Microtubule-stabilizing agent
  • Multidrug resistance
  • Peloruside
  • Persin
  • Synergy
  • Taxoid binding site
  • Tetrahydropersin

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Cite this

Microtubule-stabilizing properties of the avocado-derived toxins (+)-(R)-persin and (+)-(R)-tetrahydropersin in cancer cells and activity of related synthetic analogs. / Field, Jessica J.; Kanakkanthara, Arun; Brooke, Darby G.; Sinha, Saptarshi; Pillai, Sushila D.; Denny, William A.; Butt, Alison J.; Miller, John H.

In: Investigational New Drugs, Vol. 34, No. 3, 01.06.2016, p. 277-289.

Research output: Contribution to journalArticle

Field, Jessica J. ; Kanakkanthara, Arun ; Brooke, Darby G. ; Sinha, Saptarshi ; Pillai, Sushila D. ; Denny, William A. ; Butt, Alison J. ; Miller, John H. / Microtubule-stabilizing properties of the avocado-derived toxins (+)-(R)-persin and (+)-(R)-tetrahydropersin in cancer cells and activity of related synthetic analogs. In: Investigational New Drugs. 2016 ; Vol. 34, No. 3. pp. 277-289.
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