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Investigational New Drugs

, Volume 34, Issue 3, pp 277–289 | Cite as

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. MillerEmail author
PRECLINICAL STUDIES

Summary

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.

Keywords

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

Abbreviations

CI

Combination index

MDR

Multidrug resistance

MSA

Microtubule-stabilizing agent

P-gp

P-glycoprotein

T-persin

Tetrahydropersin

Notes

Acknowledgments

This work was supported by grants from the Cancer Society of New Zealand, Wellington Medical Research Foundation (JJF, AK, JHM), the Joy McNicoll Postgraduate Research Award in Biomedical Science (JJF), and Victoria University of Wellington (JJF, AK, JHM). We thank Dr Paraskevi Giannakkakou for the 1A9 β-tubulin mutant cell lines, and Dr Peter Northcote and Dr Jonathan Singh for the supply of the natural product peloruside A.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Jessica J. Field
    • 1
    • 2
  • Arun Kanakkanthara
    • 1
    • 3
  • Darby G. Brooke
    • 4
    • 5
  • Saptarshi Sinha
    • 1
  • Sushila D. Pillai
    • 1
  • William A. Denny
    • 5
    • 6
  • Alison J. Butt
    • 7
  • John H. Miller
    • 1
    Email author
  1. 1.Centre for Biodiscovery, School of Biological SciencesVictoria University of WellingtonWellingtonNew Zealand
  2. 2.Seattle GeneticsBothellUSA
  3. 3.Department of Pediatric and Adolescent MedicineMayo ClinicRochesterUSA
  4. 4.Cawthron InstituteNelsonNew Zealand
  5. 5.Auckland Cancer Society Research CentreThe University of AucklandAucklandNew Zealand
  6. 6.Maurice Wilkins CentreUniversity of AucklandAucklandNew Zealand
  7. 7.Cancer Research Program, Garvan Institute of Medical ResearchSt. Vincent’s HospitalDarlinghurstAustralia

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