Restoring chemotherapy and hormone therapy sensitivity by parthenolide in a xenograft hormone refractory prostate cancer model.
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.
Shanmugam
Rajasubramaniam
R
Department of Medicine, Indiana University, Indianapolis, Indiana, USA.
Jayaprakasan
Vetrichelvan
V
Gokmen-Polar
Yesim
Y
Kelich
Stephanie
S
Miller
Kathy D
KD
Yip-Schneider
Michele
M
Cheng
Liang
L
Bhat-Nakshatri
Poornima
P
Sledge
George W
GW
Nakshatri
Harikrishna
H
Zheng
Qi-Huang
QH
Miller
Michael A
MA
DeGrado
Timothy
T
Hutchins
Gary D
GD
Sweeney
Christopher J
CJ
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
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