Disease relevance of Epothilone B

• Patupilone (epothilone B) inhibits growth and survival of multiple myeloma cells in vitro and in vivo [1].
• The present study further explores the mechanisms underlying epothilone B-mediated cytotoxicity in human breast cancer cells [2].
• To further examine whether these effects were dependent on microtubule network disruption, we tested the ability of epothilone B to inhibit HIF-1alpha protein in the human ovarian cancer cell line 1A9 and its beta-tubulin mutant epothilone-resistant subclone 1A9/A8 [3].
• Ixabepilone (epothilone B analogue BMS-247550) is active in chemotherapy-naive patients with hormone-refractory prostate cancer: a Southwest Oncology Group trial S0111 [4].
• We have previously reported that the microtubule stabilizing agents (MSAs) paclitaxel, epothilone B and discodermolide induce caspase-independent cell death in non-small cell lung cancer (NSCLC) cells [5].

Psychiatry related information on Epothilone B

• A highly epothilone B-resistant A549 cell line with mutations in tubulin that confer drug dependence [6].

High impact information on Epothilone B

• In contrast, epothilone B treatment had no effect on either microtubules or HIF-1alpha nuclear accumulation in the resistant 1A9/A8 cells [3].
• Furthermore, epothilone B inhibited HIF-1 transcriptional activity in 1A9 cells, as evidenced by a hypoxia response element-luciferase reporter assay, but had no effect on HIF-1 activity in the resistant 1A9/A8 cells [3].
• Evaluation of epothilone B analog in advanced soft tissue sarcoma: a phase II study of the phase II consortium [7].
• Flavopiridol down-regulates antiapoptotic proteins and sensitizes human breast cancer cells to epothilone B-induced apoptosis [8].
• To explore the molecular mechanisms underlying the actions of Taxol and the functionally related molecule epothilone B (EpoB), we have analyzed the gene expression profiles in A549 cells in response to increasing concentrations of these microtubule-stabilizing drugs [9].

Chemical compound and disease context of Epothilone B

• Phase II trial of ixabepilone, an epothilone B analog, given daily for three days every three weeks, in metastatic breast cancer [10].
• EpoK was expressed in Escherichia coli, and the purified protein was shown to convert epothilone D to epothilone B in vitro [11].
• Melanoma cell lines A375P and DX3 were treated with temozolomide and either paclitaxel or epothilone B [12].
• Tumor necrosis factor-alpha related gene response to Epothilone B in ovarian cancer [13].

Biological context of Epothilone B

• Discodermolide and epothilone B are promising novel chemotherapeutic agentsthat induce cell death through potent stabilization of microtubules [14].
• Microtubule-stabilizing agents including Taxol, epothilone B, and discodermolide produce aneuploid populations of A549 cells in the absence of a mitotic block [15].
• We measured nitric oxide release by IFN-gamma-treated murine macrophages as an indicator of macrophage activation by epothilone B [16].
• The 12,13-diol cyclization approach for a truly stereocontrolled total synthesis of epothilone B and the synthesis of a conformationally restrained analogue [17].
• Improved synthesis of epothilone B employing alkylation of an alkyne for assembly of subunits [18].

Anatomical context of Epothilone B

• We found that epothilone B suppressed microtubule dynamics in a concentration-dependent manner coincident with mitotic block [19].
• Such aneuploid populations are diminished in an epothilone B-resistant cell line [15].
• Epothilone B stabilizes microtubuli of macrophages like taxol without showing taxol-like endotoxin activity [16].
• MDA, including epothilone B analogue (BMS-247550) and vinblastine, induced apoptosis of Bax-positive HCT116 cells in a p53-dependent manner; p53 was required for MDA-induced Bax conformational change [20].
• A Phase II trial of epothilone B analogue BMS-247550 (NSC #710428) ixabepilone, in patients with advanced pancreas cancer: a Southwest Oncology Group study [21].

Associations of Epothilone B with other chemical compounds

• Although epothilone B showed the expected effects on the microtubuli, there was no indication of macrophage stimulatory activity by epothilone B, nor did epothilone B inhibit lipopolysaccharide-mediated nitric oxide release [16].
• Bioassay data comparing the antiproliferative activity and tubulin polymerization of 43 and 54 with epothilone B (2), epothilone D (4), and paclitaxel (7) showed that the synthetic analogues were less potent than their natural counterparts, although both retain full antiproliferative activity against a paclitaxel-resistant cell line [22].
• CONCLUSIONS: Administered at doses ranging from 66% to 100% of its MTD in mice, the epothilone B derivative ixabepilone shows broad spectrum activity against a panel of pediatric tumor xenograft models [23].
• The purpose of this study was to determine activity of temozolomide combined with paclitaxel or epothilone B in vitro, and to investigate the combination of temozolomide with paclitaxel in a Phase I clinical trial [12].
• Epothilone A reacted with hydrohalic acids to C12-C13 halohydrin regioisomers (ratios: 2:1-4:1), whereas epothilone B gave under the same conditions the isomerically pure C12 halo C13 hydroxy derivative [24].

Gene context of Epothilone B

• These results indicate that in low-level epothilone B- or Taxol-resistant A549 cells, increased caveolin-1 expression occurs independently of P-glycoprotein expression [25].
• Two drug-resistant A549 cell lines (one 9-fold resistant to Taxol and the other 1.5-fold resistant to epothilone B), both of which express no P-glycoprotein, demonstrate a significant increase in the expression of caveolin-1 [25].
• On the other hand, epothilone B prevented microtubule disruption and inhibited OxLDL-dependent increases in arginase activity and attenuated OxLDL-dependent decreases in NOx [26].
• METHODS: Fresh human tumor or normal tissue disks (2 x 1 mm) from fresh surgical specimens were incorporated into fibrin-thrombin clots overlain with nutrient medium containing either 20% fetal bovine serum alone or in combination with Epothilone B, a tubulin inhibitor with antiangiogenic properties [27].
• Treatment of tumors or normal tissues with Epothilone B at doses less than 10-8 mol/L was ineffective [27].

Analytical, diagnostic and therapeutic context of Epothilone B

• These observations were confirmed by confocal microscopy, which showed impaired nuclear accumulation of HIF-1alpha in parental 1A9 cells at epothilone B concentrations that induced extensive microtubule stabilization [3].
• With Potorous tridactylis kidney epithelial (PtK2) cells examined by indirect immunofluorescence, microtubule bundles appeared more rapidly following epothilone B treatment, and there were different proportions of various mitotic aberrations following treatment with different drugs [28].
• Several phase I and phase II clinical trials are ongoing with epothilone B and BMS 247550, an epothilone B analog [29].
• Pilot study of epothilone B analog (BMS-247550) and estramustine phosphate in patients with progressive metastatic prostate cancer following castration [30].
• PURPOSE: BMS-310705, a novel semisynthetic derivative of epothilone B, is a tubulin-polymerization agent currently in phase I clinical trials for anticancer therapy [31].

References