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: Jessica J Field, Arun Kanakkanthara, Darby G Brooke, Saptarshi Sinha, Sushila D Pillai, William A Denny, Alison J Butt, John H Miller
• Journal: Investigational new drugs (Invest New Drugs) Vol. 34 Issue 3 Pg. 277-89 (06 2016) ISSN: 1573-0646 [Electronic] United States
• PMID: 26968704 (Publication Type: Journal Article)

Chemical References

• (4-nitrophenyl)deshydroxypersin
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Acetates
• Antineoplastic Agents, Phytogenic
• Fatty Alcohols
• Nitrobenzoates
• tetrahydropersin
• persin

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics)
• Acetates (pharmacology)
• Antineoplastic Agents, Phytogenic (metabolism, pharmacology)
• Binding Sites
• Binding, Competitive
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Synergism
• Fatty Alcohols (metabolism, pharmacology)
• Female
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• M Phase Cell Cycle Checkpoints (drug effects)
• Microtubules (metabolism)
• Nitrobenzoates (pharmacology)
• Ovarian Neoplasms (drug therapy, pathology)
• Persea (chemistry)