Disease relevance of C12153

• To identify tubulin residues important for epothilone binding, we have isolated two epothilone-resistant human ovarian carcinoma sublines derived in a single-step selection with epothilone A or B [1].
• In the current study, we isolated sublines of the human breast adenocarcinoma cell line MDA 435 that exhibited increasing resistance to epothilone A, a microtubule-stabilizing cytotoxic agent [2].
• Derivation of dihedral angles from CH-CH dipolar-dipolar cross-correlated relaxation rates: a C-C torsion involving a quaternary carbon atom in epothilone A bound to tubulin [3].

High impact information on C12153

• In the paclitaxel-sensitive human cell lines we examined, epothilone B had greater antiproliferative activity than epothilone A or paclitaxel, while epothilone A was usually less active than paclitaxel [4].
• This was not true for the inactive analogue of paclitaxel, baccatin III, or for an analogue of epothilone A, analogue 5, none of which stabilizes microtubules [5].
• The increased drug sensitivity did not extend to epothilone A, a drug that binds to the same site and has a mechanism of action similar to that of paclitaxel, or colcemid, a drug with an opposing mechanism of action and a distinct binding site [6].
• Thus, sarcodictyins A and B had IC50 values in the 200-500 nM range; paclitaxel, <10 nM (except in the resistant lines); and eleutherobin and epothilone A, 10-40 nM [7].
• The C7 hydroxy group of cytotoxic epothilone A was selectively oxidized using PDC [8].

Biological context of C12153

• Extending previous results, we demonstrated phosphorylation of pro-survival Bcl-x(L) in an epothilone-A resistant cell line, correlating it with drug sensitivity to tubulin-active compounds [9].
• Gene expression profiling of epothilone A-resistant cells [2].
• The high-resolution solution structure of epothilone A bound to tubulin: an understanding of the structure-activity relationships for a powerful class of antitumor agents [10].

Anatomical context of C12153

• This activity of PGA2 was similar to that of the microtubule-stabilizing agents, paclitaxel (Taxol) and epothilone A, unlike the microtubule-depolymerizing agent, colchicine, which brought about quick neurite degeneration within 3 h [11].

Associations of C12153 with other chemical compounds

• Based on their attractive in vitro biological profile epothilones have turned into important lead structures in anticancer drug discovery and hundreds of analogs and derivatives of epothilone A and B have been prepared and biologically characterized over the past four years [12].
• The synthesis of the C7-C21 fragment of epothilone A involving asymmetric alkoxyallyl- and crotylboration using alpha-pinene-derived reagents has also been described [13].

Gene context of C12153

• Hierarchical clustering of genes according to their levels of expression indicated that the majority of genes which were highly expressed in epothilone A-resistant cells but not in taxol-resistant MDR cells encode known interferon-inducible proteins [2].

Analytical, diagnostic and therapeutic context of C12153

• The binding mode of epothilone A on alpha,beta-tubulin by electron crystallography [14].
• Two groups of epothilone A-resistant cells were selected: cells which exhibited low resistance to both epothilone A and Taxol, and cells which exhibit low resistance to Taxol but high resistance to epothilone A. cDNA microarrays of epothilone A-resistant and Taxol-resistant cells were utilized to further characterize epothilone A resistance [2].

References