Disease relevance of Epothilones

• Concomitant expression of these genes in the actinomycete Streptomyces coelicolor produced epothilones A and B. Streptomyces coelicolor is more amenable to strain improvement and grows about 10-fold as rapidly as the natural producer, so this heterologous expression system portends a plentiful supply of this important agent [1].
• In contrast to taxol, epothilones retain a much greater toxicity against P-glycoprotein-expressing multiple drug resistant cells [2].
• We examined interactions of the epothilones with purified tubulin and additional cell lines, including a paclitaxel-resistant ovarian carcinoma line with an altered beta-tubulin [3].
• To produce epothilones in a more genetically amenable and rapidly growing host, we chose the closely related and best-characterized myxobacteria Myxococcus xanthus [4].
• BACKGROUND: Epothilones are a promising class of drugs in clinical trials of prostate cancer that target the microtubules, similar to taxanes, and induce apoptosis in taxane resistant tumors [5].

High impact information on Epothilones

• Epothilones A and B, two compounds that have been recently isolated from myxobacterium Sorangium cellulosum strain 90, have generated intense interest among chemists, biologists and clinicians owing to the structural complexity, unusual mechanism of interaction with microtubules and anticancer potential of these molecules [6].
• Doxorubicin treatment prevented mitotic arrest, Bcl-2 phosphorylation, and cell death caused by paclitaxel, epothilones, and vinblastine [7].
• Several structurally diverse antimitotic compounds, including the epothilones, compete with Taxol for binding to mammalian microtubules, suggesting that Taxol and these compounds share an overlapping binding site [8].
• In these cells, epothilones can principally be recognized and exported by Verapamil-sensitive efflux pumps, which are not identical to MDR1 [9].
• In addition, the structure-activity relationships of multiple taxanes and epothilones in the tubulin mutant cells can be fully explained by the model presented here, verifying its predictive value [10].

Chemical compound and disease context of Epothilones

• Phase I studies have shown that dose-limiting toxicities of epothilones are generally neurotoxicity and neutropoenia although initial studies with patupilone indicated that diarrhoea was dose limiting [11].

Biological context of Epothilones

• Furthermore, FTI and agents that prevent microtubule depolymerization, such as taxol or epothilones, act synergistically to inhibit cell growth [12].
• We now propose a common pharmacophore that unites paclitaxel, nonataxel, the epothilones, eleutherobin, and discodermolide, and rationalizes the extensive structure-activity relationship data pertinent to these compounds [13].
• Epothilones also cause cell cycle arrest at the G2-M transition leading to cytotoxicity, similar to taxol [2].
• The epothilones are equipotent and exhibit kinetics similar to taxol in inducing tubulin polymerization into microtubules in vitro (filtration, light scattering, sedimentation, and electron microscopy) and in producing enhanced microtubule stability and bundling in cultured cells [2].
• The epothilones are positioned with the macrolide ring roughly perpendicular to the heme plane and I helix, and the thiazole moiety provides key interactions that very likely are critical in determining substrate specificity [14].

Anatomical context of Epothilones

• The epothilones differ in their ability to retain activity against multidrug-resistant (MDR) cell lines and tumors where paclitaxel fails [15].
• Epothilones have effects on the cytoskeleton similar to those of the antineoplastic drug Taxol [16].
• These metabolites include several compounds of biotechnological importance such as the epothilones and chivosazols, which, respectively, stabilize the tubulin and actin skeletons of eukaryotic cells [17].
• The epothilones represent a new class of bacterial natural products with broad spectrum of antiproliferative activity against various types of human tumors and tumor cell lines [18].
• In this work, a series of Epo-resistant A549 and HeLa cell lines have been selected and analyzed [19].

Associations of Epothilones with other chemical compounds

• EpoK, a cytochrome P450 involved in biosynthesis of the anticancer agents epothilones A and B. Substrate-mediated rescue of a P450 enzyme [20].
• Their attractive preclinical profile has made epothilones important lead structures in the search for improved cytotoxic anticancer drugs and epothilone B is currently undergoing phase II clinical trials [21].
• The new analogue, containing an additional hydroxyl group at C21, exhibits advantages over other epothilones in terms of water solubility, and can serve as a readily functionalizable handle to produce other useful compounds for pertinent biological studies [22].
• When Sorangium cellulosum So ce90 is grown without XAD adsorber resin there is a steady state of epothilone A and B biosynthesis and hydroxylation of these products to epothilones E and F. This biotransformation at position C-21 of the thiazole ring is not restricted to producers of epothilones [23].
• The epothilones ixabepilone, patupilone, BMS-310705, KOS-862 and ZK-EPO are in early clinical trials for cancer treatment [11].

Gene context of Epothilones

• This strategy also allowed a selective killing of HL60/TX cells which express MDR-1, with the only difference being that the second drug, paclitaxel, was substituted for epothilones, non-Pgp substrates [24].
• Our results further provide a strong rationale for testing taxanes and epothilones in clinical trials targeting HIF-1 in cancer patients [25].
• The epoxidation of epothilones C and D to A and B, respectively, is mediated by EpoK, a cytochrome P450 enzyme encoded in the epothilone gene cluster [20].
• Enzymatic assembly of epothilones: the EpoC subunit and reconstitution of the EpoA-ACP/B/C polyketide and nonribosomal peptide interfaces [26].
• Laulimalide was active against cell lines resistant to paclitaxel or epothilones A and B on the basis of mutations in the M40 human beta-tubulin gene [27].

Analytical, diagnostic and therapeutic context of Epothilones

• Following the structural elucidation of these molecules by X-ray crystallography in 1996, several syntheses of epothilones A and B have been reported, indicative of the potential importance of these molecules in the cancer field [6].
• Generation of new epothilones by genetic engineering of a polyketide synthase in Myxococcus xanthus [28].
• A number of epothilones demonstrate a potent inhibitory effect on cell proliferation in human tumor cell lines, as well as antitumor activity in experimental animals bearing human tumor xenografts [29].

References