title: Restoring chemotherapy and hormone therapy sensitivity by parthenolide in a xenograft hormone refractory prostate cancer model.
abstract: BACKGROUND
  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).
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  These studies demonstrate parthenolide's anti-tumor and anti-angiogenic activity, and its potential to augment the efficacy of chemotherapy and hormonal therapy.
authors.affiliation: Department of Medicine, Indiana University, Indianapolis, Indiana, USA.
authors.forename: Rajasubramaniam
authors.initials: R
authors.lastname: Shanmugam
authors.forename: Vetrichelvan
authors.initials: V
authors.lastname: Jayaprakasan
authors.forename: Yesim
authors.initials: Y
authors.lastname: Gokmen-Polar
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kelich
authors.forename: Kathy D
authors.initials: KD
authors.lastname: Miller
authors.forename: Michele
authors.initials: M
authors.lastname: Yip-Schneider
authors.forename: Liang
authors.initials: L
authors.lastname: Cheng
authors.forename: Poornima
authors.initials: P
authors.lastname: Bhat-Nakshatri
authors.forename: George W
authors.initials: GW
authors.lastname: Sledge
authors.forename: Harikrishna
authors.initials: H
authors.lastname: Nakshatri
authors.forename: Qi-Huang
authors.initials: QH
authors.lastname: Zheng
authors.forename: Michael A
authors.initials: MA
authors.lastname: Miller
authors.forename: Timothy
authors.initials: T
authors.lastname: DeGrado
authors.forename: Gary D
authors.initials: GD
authors.lastname: Hutchins
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Sweeney
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging / Q000188:drug therapy*; D009570:Nitriles; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy*; D011877:Radionuclide Imaging; D012717:Sesquiterpenes / Q000494:pharmacology*; D047990:TNF Receptor-Associated Factor 1 / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology; D014105:Tosyl Compounds; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000726:Androgen Antagonists; D000813:Anilides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000972:Antineoplastic Agents, Phytogenic; D001952:Bridged-Ring Compounds; D016328:NF-kappa B; D009570:Nitriles; D012717:Sesquiterpenes; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D043823:Taxoids; D014105:Tosyl Compounds; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D000077143:Docetaxel; C080625:taxane; C002669:parthenolide; C053541:bicalutamide; D048031:JNK Mitogen-Activated Protein Kinases