Targeting Nuclear Factor kappa B for the Treatment of Prostate Cancer
Abstract
Our hypothesis is that inhibition of NFkB will be an effective treatment strategy for hormone refractory prostate cancer. We have identified that constitutive NFkB DNA in prostate cancer cell lines and Human Umbilical Venous Endothelial Cells (HUVECs). Moreover, we have found that parthenolide, is able to prevent NFkB DNA binding and inhibit in vitro cancer cell proliferation and angiogenesis as well as in vivo angiogenesis in a manigel plug assay. Our work to date has shown that TRAK-1 and c-JUN are decreased in both hormone sensitive and hormone resistant cell lines by 6 hours of parthenolide treatment This was done by use of a NFkB gene array. We have also shown that TRAF-1 is decreased by parthenolide in HUVECs. We have demonstrated that this corresponded to decreased NFkB DNA binding when whole cell extracts were exposed to parthenolide. The NFkB DNA binding experiments will be repeated using nuclear extracts. The parthenolide serum level achieved in mice that decreased in vivo angiogenesis was approximately 0.4 uM. In essence we have shown that genes change in response to parthenolide treatment and our efforts will focus trying to confirm this at the protein level and determine whether other genes are affected at a lower concentration that may be independent of NFkB. This is due to the active in vitro level being 4 uM. Our first in vivo experiments suggested that parthenolide had no significant activity as a single agent, but as much activity as docetaxel. However, the combination of parthenolide and docetaxel had a pronounced effect. We need to perform further experiments to confirm this. Finally we have performed immunohistochemical staining of 97 prostate cancer specimens and noted that there is a graded increase in the presence of activated NFkB from normal prostate tissue to cancer specimens.
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 2003
- Accession Number
- ADA415323
Entities
People
- Christopher Sweeney
Organizations
- Indiana University