The taccalonolides: Microtubule stabilizers that circumvent clinically relevant taxane resistance mechanisms

April L Risinger, Evelyn M. Jackson, Lisa A. Polin, Gregory L. Helms, Desiree A. LeBoeuf, Patrick A. Joe, Elizabeth Hopper-Borge, Richard F. Ludueña, Gary D. Kruh, Susan L Mooberry

Research output: Contribution to journalArticle

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Abstract

The taccalonolides are a class of structurally and mechanistically distinct microtubule-stabilizing agents isolated from Tacca chantrieri. A crucial feature of the taxane family of microtubule stabilizers is their susceptibility to cellular resistance mechanisms including overexpression of P-glycoprotein (Pgp), multidrug resistance protein 7 (MRP7), and the βIII isotype of tubulin. The ability of four taccalonolides, A, E, B, and N, to circumvent these multidrug resistance mechanisms was studied. Taccalonolides A, E, B, and N were effective in vitro against cell lines that overexpress Pgp and MRP7. In addition, taccalonolides A and E were highly active in vivo against a doxorubicin- and paclitaxel-resistant Pgp-expressing tumor, Mam17/ADR. An isogenic HeLa-derived cell line that expresses the βIII isotype of tubulin was generated to evaluate the effect of βIII-tubulin on drug sensitivity. When compared with parental HeLa cells, the βIII-tubulin-overexpressing cell line was less sensitive to paclitaxel, docetaxel, epothilone B, and vinblastine. In striking contrast, the βIII-tubulin-overexpressing cell line showed greater sensitivity to all four taccalonolides. These data cumulatively suggest that the taccalonolides have advantages over the taxanes in their ability to circumvent multiple drug resistance mechanisms. The ability of the taccalonolides to overcome clinically relevant mechanisms of drug resistance in vitro and in vivo confirms that the taccalonolides represent a valuable addition to the family of microtubule-stabilizing compounds with clinical potential.

Original languageEnglish (US)
Pages (from-to)8881-8888
Number of pages8
JournalCancer Research
Volume68
Issue number21
DOIs
StatePublished - Nov 1 2008

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Tubulin
Microtubules
P-Glycoprotein
P-Glycoproteins
Cell Line
docetaxel
Multiple Drug Resistance
Paclitaxel
HeLa Cells
Dioscoreaceae
Taxoids
Vinblastine
Excipients
Drug Resistance
Doxorubicin
taxane
Pharmaceutical Preparations
Neoplasms
In Vitro Techniques

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

The taccalonolides : Microtubule stabilizers that circumvent clinically relevant taxane resistance mechanisms. / Risinger, April L; Jackson, Evelyn M.; Polin, Lisa A.; Helms, Gregory L.; LeBoeuf, Desiree A.; Joe, Patrick A.; Hopper-Borge, Elizabeth; Ludueña, Richard F.; Kruh, Gary D.; Mooberry, Susan L.

In: Cancer Research, Vol. 68, No. 21, 01.11.2008, p. 8881-8888.

Research output: Contribution to journalArticle

Risinger, AL, Jackson, EM, Polin, LA, Helms, GL, LeBoeuf, DA, Joe, PA, Hopper-Borge, E, Ludueña, RF, Kruh, GD & Mooberry, SL 2008, 'The taccalonolides: Microtubule stabilizers that circumvent clinically relevant taxane resistance mechanisms', Cancer Research, vol. 68, no. 21, pp. 8881-8888. https://doi.org/10.1158/0008-5472.CAN-08-2037
Risinger, April L ; Jackson, Evelyn M. ; Polin, Lisa A. ; Helms, Gregory L. ; LeBoeuf, Desiree A. ; Joe, Patrick A. ; Hopper-Borge, Elizabeth ; Ludueña, Richard F. ; Kruh, Gary D. ; Mooberry, Susan L. / The taccalonolides : Microtubule stabilizers that circumvent clinically relevant taxane resistance mechanisms. In: Cancer Research. 2008 ; Vol. 68, No. 21. pp. 8881-8888.
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