Taccalonolides E and A: Plant-derived steroids with microtubule-stabilizing activity

During the course of a mechanism-based screening program designed to identify new microtubule-disrupting agents from natural products, we identified a crude extract from Tacca chantrieri that initiated Taxol-like microtubule bundling. Bioassay-directed purification of the extract yielded the highly...

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Published inCancer research (Chicago, Ill.) Vol. 63; no. 12; pp. 3211 - 3220
Main Authors TINLEY, Tina L, RANDALL-HLUBEK, Deborah A, LEAL, Rachel M, JACKSON, Evelyn M, CESSAC, James W, QUADA, James C, HEMSCHEIDT, Thomas K, MOOBERRY, Susan L
Format Journal Article
LanguageEnglish
Published Philadelphia, PA American Association for Cancer Research 15.06.2003
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Abstract During the course of a mechanism-based screening program designed to identify new microtubule-disrupting agents from natural products, we identified a crude extract from Tacca chantrieri that initiated Taxol-like microtubule bundling. Bioassay-directed purification of the extract yielded the highly oxygenated steroids taccalonolides E and A. The taccalonolides caused an increased density of cellular microtubules in interphase cells and the formation of thick bundles of microtubules similar to the effects of Taxol. Mitotic cells exhibited abnormal mitotic spindles containing three or more spindle poles. The taccalonolides were evaluated for antiproliferative effects in drug-sensitive and multidrug-resistant cell lines. The data indicate that taccalonolide E is slightly more potent than taccalonolide A in drug-sensitive cell lines and that both taccalonolides are effective inhibitors of cell proliferation. Both taccalonolides are poorer substrates for transport by P-glycoprotein than Taxol. The ability of the taccalonolides to circumvent mutations in the Taxol-binding region of beta-tubulin was examined using the PTX 10, PTX 22, and 1A9/A8 cell lines. The data suggest little cross-resistance of taccalonolide A as compared with Taxol, however, the data from the PTX 22 cell line indicate a 12-fold resistance to taccalonolide E, suggesting a potential overlap of binding sites. Characteristic of agents that disrupt microtubules, the taccalonolides caused G(2)-M accumulation, Bcl-2 phosphorylation, and initiation of apoptosis. The taccalonolides represent a novel class of plant-derived microtubule-stabilizers that differ structurally and biologically from other classes of microtubule-stabilizers.
AbstractList During the course of a mechanism-based screening program designed to identify new microtubule-disrupting agents from natural products, we identified a crude extract from Tacca chantrieri that initiated Taxol-like microtubule bundling. Bioassay-directed purification of the extract yielded the highly oxygenated steroids taccalonolides E and A. The taccalonolides caused an increased density of cellular microtubules in interphase cells and the formation of thick bundles of microtubules similar to the effects of Taxol. Mitotic cells exhibited abnormal mitotic spindles containing three or more spindle poles. The taccalonolides were evaluated for antiproliferative effects in drug-sensitive and multidrug-resistant cell lines. The data indicate that taccalonolide E is slightly more potent than taccalonolide A in drug-sensitive cell lines and that both taccalonolides are effective inhibitors of cell proliferation. Both taccalonolides are poorer substrates for transport by P-glycoprotein than Taxol. The ability of the taccalonolides to circumvent mutations in the Taxol-binding region of beta-tubulin was examined using the PTX 10, PTX 22, and 1A9/A8 cell lines. The data suggest little cross-resistance of taccalonolide A as compared with Taxol, however, the data from the PTX 22 cell line indicate a 12-fold resistance to taccalonolide E, suggesting a potential overlap of binding sites. Characteristic of agents that disrupt microtubules, the taccalonolides caused G(2)-M accumulation, Bcl-2 phosphorylation, and initiation of apoptosis. The taccalonolides represent a novel class of plant-derived microtubule-stabilizers that differ structurally and biologically from other classes of microtubule-stabilizers.
Author QUADA, James C
TINLEY, Tina L
RANDALL-HLUBEK, Deborah A
JACKSON, Evelyn M
HEMSCHEIDT, Thomas K
MOOBERRY, Susan L
LEAL, Rachel M
CESSAC, James W
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Issue 12
Keywords Antineoplastic agent
Human
Steroid
Monocotyledones
Root
Extract
In vitro
Biological activity
Medicinal plant
Tubulin
Animal
Angiospermae
Cell cycle
Established cell line
Plant origin
Cytoskeleton
Spermatophyta
Microtubule
Mechanism of action
Antimitotic
Taccaceae
Tumor cell
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PublicationTitle Cancer research (Chicago, Ill.)
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Snippet During the course of a mechanism-based screening program designed to identify new microtubule-disrupting agents from natural products, we identified a crude...
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SubjectTerms Animals
Antineoplastic agents
Antineoplastic Agents - isolation & purification
Antineoplastic Agents - pharmacology
Antineoplastic Agents, Phytogenic - isolation & purification
Antineoplastic Agents, Phytogenic - pharmacology
Apoptosis - drug effects
Biological and medical sciences
Biopolymers
Breast Neoplasms - pathology
Cell Nucleus - drug effects
Cells, Cultured - drug effects
Cells, Cultured - ultrastructure
Centrosome - drug effects
Chemotherapy
Drug Resistance, Neoplasm
Enzyme Activation - drug effects
Female
General pharmacology
HeLa Cells - drug effects
HeLa Cells - ultrastructure
Humans
Interphase - drug effects
MAP Kinase Signaling System - drug effects
Medical sciences
Microtubule Proteins - metabolism
Microtubules - drug effects
Mitosis - drug effects
Molecular Structure
Muscle, Smooth - cytology
Ovarian Neoplasms - pathology
Pharmacognosy. Homeopathy. Health food
Pharmacology. Drug treatments
Phosphorylation - drug effects
Protein Processing, Post-Translational - drug effects
Proto-Oncogene Proteins c-bcl-2 - metabolism
Rats
Rhizome - chemistry
Spindle Apparatus - drug effects
Steroids - isolation & purification
Steroids - pharmacology
Tumor Cells, Cultured - drug effects
Tumor Cells, Cultured - ultrastructure
Title Taccalonolides E and A: Plant-derived steroids with microtubule-stabilizing activity
URI https://www.ncbi.nlm.nih.gov/pubmed/12810650
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Volume 63
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