taxane and parthenolide

Nuclear Factor kappa B (NFkappaB) is a eukaryotic transcription factor that is constitutively active in human cancers and can be inhibited by the naturally occurring sesquiterpene lactone, parthenolide (P).. The in vitro effects of P were assessed using the androgen independent cell line, CWR22Rv1, and human umbilical endothelial cells (HUVECs). The in vivo activity of P as a single agent and its ability to augment the efficacy of docetaxel and the anti-androgen, bicalutamide, were determined using the CWR22Rv1 xenograft model.. Parthenolide at low micromolar concentration inhibited proliferation of CWR22Rv1 and HUVEC cells, promoted apoptosis and abrogated NFkappaB-DNA binding. Parthenolide downregulated anti-apoptotic genes under NFkappaB control, TRAF 1 and 2, and promoted sustained activation of c-jun-NH2 kinase (JNK). Parthenolide also augmented the in vivo efficacy of docetaxel and restored sensitivity to anti-androgen therapy.. These studies demonstrate parthenolide's anti-tumor and anti-angiogenic activity, and its potential to augment the efficacy of chemotherapy and hormonal therapy.

Topics: Androgen Antagonists; Anilides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents, Phytogenic; Bridged-Ring Compounds; Cell Line, Tumor; Docetaxel; Drug Synergism; Endothelium, Vascular; Fibroblast Growth Factor 2; Humans; JNK Mitogen-Activated Protein Kinases; Male; Mice; Mice, Nude; Neovascularization, Pathologic; NF-kappa B; Nitriles; Prostatic Neoplasms; Radionuclide Imaging; Sesquiterpenes; Taxoids; TNF Receptor-Associated Factor 1; TNF Receptor-Associated Factor 2; Tosyl Compounds; Umbilical Veins; Vascular Endothelial Growth Factor A