Taccalonolide Microtubule-Stabilizing Agent

Category: Biology and Medicine

Reference Number: 00219

Description

This new microtubule-stabilizing agent is an effective cytotoxin against many cancer cells in vitro. Bioassay-directed purification of the crude lipophilic extract yielded a steroid with paclitaxel-like microtubule-stabilizing activity. Non-transformed cells treated with the agent exhibited interphase arrest and extensive microtubule bundling. Many of the microtubule bundles were located in the cell periphery, apparently nucleated independent of the microtubule-organizing center. The compound also initiated the breakdown of the nucleus into micronuclei. Abnormal, often tripolar, mitotic spindles were seen in dividing cells. In transformed cells, the agent caused mitotic arrest, coincident with the formation of abnormal mitotic spindles. Cells treated with the compound underwent apoptotic cell death following Bcl-2 phosphorylation. The compound was found to be an effective inhibitor of proliferation in a variety of cell types with IC50's in the low micro molar range. Data suggest that this new microtubule-stabilizing agent is a poor substrate for P-glycoprotein-mediated drug transport and in this regard may have advantages over Taxol®. It represents only the sixth class of compounds that has been found (after extensive searching by many academic and industrial groups) that possesses microtubule-stabilizing activity, the first microtubule-stabilizing agent to be discovered in higher plants since Taxol®, and the first natural steroid to exhibit these microtubule effects.

Applications

Cancer therapy.

Main Advantages

This discovery represents the identification of a new class of agents with Taxol®-like activity. To date, compounds that have the same or similar mechanism of action have broad antitumor activity. The chemical structure of taccalonolide A is amenable to analog production and chemical semi-synthesis. Taccalonolide A inhibits proliferation of cancer cells and causes cell death via initiation of apoptosis. In addition, the plant source of this new agent represents a renewable resource. Root cuttings may be removed from live plants without damaging the plant.

Inventor(s)

Thomas K. Hemscheidt
Chemistry/Cancer Research Center of Hawai'i
Susan L. Mooberry
Southwest Foundation for Biomedical Research
(formerly with the Cancer Research Center of Hawai'i)

Contact Information

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Honolulu, HI 96822