taxane and bicalutamide

Taxane based chemotherapy is the standard of care treatment in castration resistant prostate cancer (CRPC). There is convincing evidence that taxane therapy affects androgen receptor (AR) but the exact mechanisms have to be further elucidated. Our studies identified c-jun as a crucial key player which interacts with AR and thus determines the outcome of the taxane therapy given. Docetaxel (Doc) and paclitaxel (Pac) agents showed different effects on LNCaP and LNb4 evidenced by alteration in the protein and mRNA levels of c-jun, AR and PSA. Docetaxel-induced phophorylation of c-jun occurred before JNK phosphorylation which suggests that c-jun phosphorylation is independent of JNK pathways in prostate cancer cells. A xenograft study showed that mice treated with Pac and bicalutamide showed worse outcome supporting our hypothesis that upregulation of c-jun might act as a potent antiapoptotic factor. We observed in our in vitro studies an inverse regulation of PSA- and AR-mRNA levels in Doc treated LNb4 cells. This was also seen for kallikrein 2 (KLK 2) which followed the same pattern. Given the fact that response to taxane therapy is measured by PSA decrease we have to consider that this might not reflect the true activity of AR in CRPC patients.

Topics: Anilides; Animals; Apoptosis; Bridged-Ring Compounds; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Flow Cytometry; Humans; Immunohistochemistry; Male; Mice; Mice, Nude; Nitriles; Prostatic Neoplasms; Protein Binding; Proto-Oncogene Proteins c-jun; Real-Time Polymerase Chain Reaction; Receptors, Androgen; RNA, Small Interfering; Taxoids; Tosyl Compounds

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