Penta-O-galloyl-beta-D-glucose induces G1 arrest and DNA replicative S-phase arrest independently of cyclin-dependent kinase inhibitor 1A, cyclin-dependent kinase inhibitor 1B and P53 in human breast cancer cells and is orally active against triple negative xenograft growth.
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17-allyamino-17-demethoxygeldanamycin treatment results in a magnetic resonance spectroscopy-detectable elevation in choline-containing metabolites associated with increased expression of choline transporter SLC44A1 and phospholipase A2.
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The Discodermia calyx toxin calyculin a enhances cyclin D1 phosphorylation and degradation, and arrests cell cycle progression in human breast cancer cells.
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Alterations in tumor necrosis factor signaling pathways are associated with cytotoxicity and resistance to taxanes: a study in isogenic resistant tumor cells.
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INTRODUCTION: The taxanes paclitaxel and docetaxel are widely used in the treatment of breast, ovarian, and other cancers. Although their cytotoxicity has been attributed to cell-cycle arrest through stabilization of microtubules, the mechanisms by which tumor cells die remains unclear. Paclitaxel has been shown to induce soluble tumor necrosis factor alpha (sTNF-alpha) production in macrophages, but the involvement of TNF production in taxane cytotoxicity or resistance in tumor cells has not been established. Our study aimed to correlate alterations in the TNF pathway with taxane cytotoxicity and the acquisition of taxane resistance. METHODS: MCF-7 cells or isogenic drug-resistant variants (developed by selection for surviving cells in increasing concentrations of paclitaxel or docetaxel) were assessed for sTNF-alpha production in the absence or presence of taxanes by enzyme-linked immunosorbent assay (ELISA) and for sensitivity to docetaxel or sTNF-alpha by using a clonogenic assay (in the absence or presence of TNFR1 or TNFR2 neutralizing antibodies). Nuclear factor (NF)-kappaB activity was also measured with ELISA, whereas gene-expression changes associated with docetaxel resistance in MCF-7 and A2780 cells were determined with microarray analysis and quantitative reverse transcription polymerase chain reaction (RTqPCR). RESULTS: MCF-7 and A2780 cells increased production of sTNF-alpha in the presence of taxanes, whereas docetaxel-resistant variants of MCF-7 produced high levels of sTNF-alpha, although only within a particular drug-concentration threshold (between 3 and 45 nM). Increased production of sTNF-alpha was NF-kappaB dependent and correlated with decreased sensitivity to sTNF-alpha, decreased levels of TNFR1, and increased survival through TNFR2 and NF-kappaB activation. The NF-kappaB inhibitor SN-50 reestablished sensitivity to docetaxel in docetaxel-resistant MCF-7 cells. Gene-expression analysis of wild-type and docetaxel-resistant MCF-7, MDA-MB-231, and A2780 cells identified changes in the expression of TNF-alpha-related genes consistent with reduced TNF-induced cytotoxicity and activation of NF-kappaB survival pathways. CONCLUSIONS: We report for the first time that taxanes can promote dose-dependent sTNF-alpha production in tumor cells at clinically relevant concentrations, which can contribute to their cytotoxicity. Defects in the TNF cytotoxicity pathway or activation of TNF-dependent NF-kappaB survival genes may, in contrast, contribute to taxane resistance in tumor cells. These findings may be of strong clinical significance. (+info)