Disease relevance of Discodermolide

• Late activation of apoptotic pathways plays a negligible role in mediating the cytotoxic effects of discodermolide and epothilone B in non-small cell lung cancer cells [1].
• Synergistic suppression of microtubule dynamics by discodermolide and paclitaxel in non-small cell lung carcinoma cells [2].
• Potentiation of taxol efficacy and by discodermolide in ovarian carcinoma xenograft-bearing mice [3].
• In addition, SKOV-3 xenograft-bearing mice were treated with either Taxol, discodermolide, or a combination of both drugs given concurrently to evaluate the antitumor efficacy and toxicity of this combination [3].
• Discodermolide was effective in suppressing the graft-versus-host splenomegaly response of BALB/c----CB6F1 (BALB/c X C57BL/6J)F1 grafted mice at 5.0, 2.5, and 1.25 mg/kg, when administered as daily, i.p. injections, for 7 days [4].

High impact information on Discodermolide

• The mechanism of cytotoxic action for paclitaxel-i.e., the stabilization of microtubules leading to mitotic arrest-is now shared by four recently identified natural products, eleutherobin, epothilones A and B, and discodermolide [5].
• Despite their apparently similar binding sites on microtubules, discodermolide acts synergistically with paclitaxel to inhibit proliferation of A549 human lung cancer cells (L. Martello et al., Clin. Cancer Res., 6: 1978-1987, 2000) [2].
• Discodermolide and paclitaxel also synergistically blocked cell cycle progression at G(2)-M (41, 9.6, and 16% for both drugs together, for discodermolide alone, and for paclitaxel alone, respectively; CI = 0.59), and they synergistically enhanced apoptosis (CI = 0.85) [2].
• Possible death receptor dependency was investigated in H460 cells stably overexpressing dominant-negative FADD, which failed to reduce the cytotoxic effects of discodermolide and epothilone B [1].
• Interestingly, caspase inhibition did not rescue cells from discodermolide or epothilone B-induced cell death [1].

Biological context of Discodermolide

• Recently, three natural products have been identified, the epothilones, eleutherobin, and discodermolide, whose mechanism of action is similar to that of Taxol in that they stabilize microtubules and block cells in the mitotic phase of the cell cycle [6].
• CONCLUSIONS: The synergistic activity of Taxol and discodermolide in cells is most potent at drug concentrations that result in drug-induced aneuploidy rather than mitotic arrest [3].
• Intracellular microtubules were reorganized into bundles in interphase cells much more rapidly after discodermolide treatment compared with paclitaxel treatment [7].
• Discodermolide suppressed the proliferative responses of splenocytes in the murine two-way mixed lymphocyte reaction (MLR) and concanavalin A stimulated cultures, with IC50 values of 0.24 microM and 0.19 microM, respectively [8].
• Treatment of normal, nongrafted mice with similar high dosages of discodermolide (5.0 mg/kg) for 4 days did not affect the primary antibody response of mice immunized with sheep red blood cells as measured by hemagglutination activity of their serum [4].

Anatomical context of Discodermolide

• Taxol and discodermolide represent a synergistic drug combination in human carcinoma cell lines [6].
• The effects of discodermolide on the reorganization of the microtubules of Potorous tridactylis kidney epithelial cells were examined at different times [7].
• Splenocytes obtained from discodermolide-treated, allogeneic grafted mice were suppressed in their ability to respond in vitro to optimal mitogenic concentrations of concanavalin A, and natural-killer-cell activity directed against YAC-1 tumor cells, compared with vehicle-treated, allogeneic grafted control mice [4].
• Discodermolide-treated breast carcinoma cells displayed spectacular rearrangement of the microtubule cytoskeleton, including extensive microtubule bundling [9].
• Discodermolide was equally effective, compared with cyclosporine, in suppressing the PMA-ionomycin induced proliferation of purified, murine T cells, with IC50 values of 9.0 nM and 14.0 nM for discodermolide and CsA, respectively [8].

Associations of Discodermolide with other chemical compounds

• To determine the mechanisms by which paclitaxel, discodermolide, and BMS-247550 activate hPXR, a mammalian two-hybrid assay was done using VP16SRC-1 (coactivator) and GAL4-SXR [10].
• Blockage of cell proliferation by discodermolide appears to occur at the G2/M interface of the cell cycle, similar to that observed with other types of antiproliferative drugs (i.e., doxorubicin) [11].

Gene context of Discodermolide

• Although some of these differences between Taxol and discodermolide were dose dependent, only discodermolide produced a doxorubicin-like induction of a senescence phenotype, including a senescence-associated beta-galactosidase activity, up-regulation of PAI-1 and p66Shc, and a strong, sustained, Erk1/2 activation [12].
• In vitro, discodermolide polymerizes purified tubulin potently in the absence of MAPs [13].
• Multidrug-resistant human colon and ovarian carcinoma cells overexpressing P-glycoprotein, which are 900- and 2800-fold resistant to paclitaxel, respectively, relative to the parental lines, retained significant sensitivity to discodermolide (25- and 89-fold more resistant relative to the parental lines) [7].
• Similarly, discodermolide suppressed the proliferative responses of human peripheral blood leukocytes (PBL) in the two-way MLR, and Con A and phytohemagglutinin mitogenesis [8].
• A strategy for exploiting the pseudosymmetry of the C1-C13 stretch of discodermolide [14].

Analytical, diagnostic and therapeutic context of Discodermolide

• Discodermolide is a new microtubule-targeted antimitotic drug in Phase I clinical trials that, like paclitaxel, stabilizes microtubule dynamics and enhances microtubule polymer mass in vitro and in cells [2].
• Flow cytometry revealed that concurrent exposure of A549 cells to Taxol and discodermolide at doses that do not induce mitotic arrest caused an increase in the hypodiploid population, thereby indicating that a possible mechanism for the observed synergy is the potentiation of apoptosis [6].
• A quantitative evaluation of the effects of inhibitors of tubulin assembly on polymerization induced by discodermolide, epothilone B, and paclitaxel [15].
• Immunosuppression by discodermolide [11].

References