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 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.
Tinley
Tina L
TL
Department of Physiology and Medicine, Southwest Foundation for Biomedical Research, San Antonio, Texas 78227, USA.
Randall-Hlubek
Deborah A
DA
Leal
Rachel M
RM
Jackson
Evelyn M
EM
Cessac
James W
JW
Quada
James C
JC
Hemscheidt
Thomas K
TK
Mooberry
Susan L
SL
D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001704:Biopolymers; D001943:Breast Neoplasms / Q000473:pathology; D002467:Cell Nucleus / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000648:ultrastructure; D018385:Centrosome / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006367:HeLa Cells / Q000187:drug effects / Q000648:ultrastructure; D006801:Humans; D007399:Interphase / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008868:Microtubule Proteins / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects*; D008938:Mitosis / Q000187:drug effects; D015394:Molecular Structure; D009130:Muscle, Smooth / Q000166:cytology; D010051:Ovarian Neoplasms / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D027343:Rhizome / Q000737:chemistry; D008941:Spindle Apparatus / Q000187:drug effects; D013256:Steroids / Q000302:isolation & purification / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000648:ultrastructure
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D001704:Biopolymers; D008868:Microtubule Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013256:Steroids; C475870:taccalonolide A; C475869:taccalonolide E