The taccalonolides: microtubule stabilizers that circumvent clinically relevant taxane resistance mechanisms.
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 betaIII 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 betaIII isotype of tubulin was generated to evaluate the effect of betaIII-tubulin on drug sensitivity. When compared with parental HeLa cells, the betaIII-tubulin-overexpressing cell line was less sensitive to paclitaxel, docetaxel, epothilone B, and vinblastine. In striking contrast, the betaIII-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.
Risinger
April L
AL
Department of Physiology and Medicine, Southwest Foundation for Biomedical Research, University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA.
Jackson
Evelyn M
EM
Polin
Lisa A
LA
Helms
Gregory L
GL
LeBoeuf
Desiree A
DA
Joe
Patrick A
PA
Hopper-Borge
Elizabeth
E
Ludueña
Richard F
RF
Kruh
Gary D
GD
Mooberry
Susan L
SL
D000818:Animals; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D008870:Microtubules / Q000187:drug effects*; D013256:Steroids / Q000494:pharmacology*; D043823:Taxoids / Q000494:pharmacology*
D013256:Steroids; D043823:Taxoids; C475870:taccalonolide A; C475869:taccalonolide E