desoxyepothilone-b and Lung-Neoplasms

Desoxyepothilone B (dEpoB), currently in clinical trials, is a novel microtubule inhibitor with similar mode-of-action to paclitaxel (Taxol). Intriguingly, it is effective in some cell lines and tumor xenografts refractory to Taxol. The purpose of this study is to compare signaling induced by the two drugs and identify a molecular basis for increased efficacy of dEpoB in resistant lines. The importance of ERK signaling, already established for Taxol, was shown for dEpoB and other G2-blocking agents. However, a role in differential sensitivity was not observed. Affymetrix analysis shows similar gene modulation by either agent, alone or in combination with MEK inhibitor. Differential sensitivity in a set of Taxol-resistant lines correlated to the expression of P-glycoprotein (P-gp), and its importance was demonstrated directly. These results suggest that Taxol and dEpoB elicit similar cell death pathways, and the increased efficacy of dEpoB in resistant tumor lines lies in differential susceptibility to P-gp.

Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Breast Neoplasms; Cell Death; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Lung Neoplasms; Paclitaxel; Signal Transduction; Tumor Cells, Cultured

A new epothilone, 10,11-didehydroepothilone D (5), was isolated from a strain of the heterologous host Myxococcus xanthus genetically engineered to produce epothilone D (4). The structure of 5 was determined from NMR and MS data. The epothilone polyketide synthase was further modified in a recombinant M. xanthus strain to produce 5 as the major epothilone-related metabolite. The cytotoxicity of 5 against a panel of tumor cell lines, including several with multidrug resistance, and its effect on tubulin polymerization were comparable to epothilone D (4).

Topics: Antineoplastic Agents; Base Sequence; Binding Sites; Breast Neoplasms; Drug Screening Assays, Antitumor; Epothilones; Epoxy Compounds; Female; Genetic Engineering; Glioma; HL-60 Cells; Humans; Inhibitory Concentration 50; Leukemia, Promyelocytic, Acute; Leukemia, T-Cell; Lung Neoplasms; Mass Spectrometry; Molecular Sequence Data; Molecular Structure; Multienzyme Complexes; Myxococcus xanthus; Nuclear Magnetic Resonance, Biomolecular; Thiazoles; Tubulin; Tumor Cells, Cultured