[show abstract][hide abstract] ABSTRACT: The taccalonolides are a unique class of microtubule stabilizers that do not bind directly to tubulin. Three new taccalonolides, Z, AA, and AB, along with two known compounds, taccalonolides R and T, were isolated from Tacca chantrieri and Tacca integrifolia. Taccalonolide structures were determined by 1D and 2D NMR methods. The biological activities of the new taccalonolides, as well as taccalonolides A, B, E, N, R, and T, were evaluated. All nine taccalonolides display microtubule stabilizing activity, but profound differences in antiproliferative potencies were noted, with IC(50) values ranging from the low nanomolar range for taccalonolide AA (32 nM) to the low micromolar range for taccalonolide R (13 μM). These studies demonstrate that diverse taccalonolides possess microtubule stabilizing properties and that significant structure-activity relationships exist. In vivo antitumor evaluations of taccalonolides A, E, and N show that each of these molecules has in vivo antitumor activity.
Journal of Medicinal Chemistry 08/2011; 54(17):6117-24. · 5.61 Impact Factor
[show abstract][hide abstract] 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 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.
Cancer Research 12/2008; 68(21):8881-8. · 8.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: During the course of a mechanism-based screening program aimed at identifying new antimitotic agents, a novel microtubule depolymerizing piperazine derivative, 1-(5-chloro-2-methoxybenzoyl)-4-(3-chlorophenyl) piperazine, was identified. The compound, designated CB694, caused inhibition of proliferation of a wide range of cancer cell lines, with an average IC50 of 85 nM. A multidrug-resistant cell line was sensitive to inhibition by CB694, suggesting that this compound is a poor substrate for transport by P-glycoprotein. CB694 caused formation of abnormal mitotic structures in HeLa cells. Specifically, CB694 caused a concentration-dependent increase in bipolar spindles with lagging chromosomes and, with slightly higher concentrations, formation of multipolar mitotic spindles. These mitotic abnormalities occurred at concentrations that did not cause significant changes in the appearance or quantity of interphase microtubules. Coincident with the formation of abnormal mitotic spindles, CB694 caused G2/M arrest. CB694 inhibited the assembly of purified tubulin with an IC50 of 2.3 microM. Colchicine binding was strongly inhibited by CB694, suggesting that it binds to tubulin at the colchicine site. Bcl-2 phosphorylation and activation of ERK and JNK and caspase 3-dependent cleavage of PARP were observed in MDA-MB-435 cells treated with CB694. CB694 caused phosphorylation of Aurora A within 8 hr of treatment, and increases in Aurora A protein levels were coincident with mitotic accumulation. The efficacy of CB694 against a syngeneic murine transplantable solid tumor, Mammary 16/C, was also evaluated. CB694 was well tolerated and showed antitumor activity.
International Journal of Cancer 03/2006; 118(4):1032-40. · 6.20 Impact Factor