Targeting Nuclear Factor kappa B for the Treatment of Prostate Cancer
Abstract
This report details the work conducted as part of the New Investigator Award. In essence, we have shown the relevance of the transcription factor, Nuclear Factor kappa beta (NFkB) to prostate cancer and that inhibition with parthenolide results in anti-cancer activity. To date we have shown that NFkB is constitutively active in prostate cancer cell lines and endothelial cells and that NFkB DNA binding is inhibited by parthenolide. Moreover, we have found that NFkB is over-expressed in human prostatectomy specimens at both the prostatic intraepithelial neoplasia and invasive adenocarcinoma stages. With the use of cDNA array technology we have shown that multiple genes associated with the hallmarks of cancer and that are under NFkB control are decreased when cancer and endothelial cells are treated with parthenolide. Western blot analysis confirmed these findings at the protein level. We have subsequently shown that parthenolide is able to decrease cancer cell proliferation and enhance the cytotoxic effect of taxanes in vitro. Finally, we have shown that parthenolide is binactive in vivo as it is able to inhibit angiogenesis as a single agent, enhance the cytotoxic effects of docetaxel and restore sensitivity of the hormone independent cell line, CWR22Rv1, to the anti-androgen, bicalutamide. More recently, we demonstrated the ability of parthenolide to activate JNK in vitro and in vivo. However, our in vivo work in collaboration with the NCI through the RAID program revealed the poor oral biovailability of parthenolide. With these findings in hand, we have directed our efforts to developing a water soluble analogue that will be more suitable for clinical development as well as turning our attention to defining the drug's mechanism of action.
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 2005
- Accession Number
- ADA442136
Entities
People
- Christopher Sweeney
Organizations
- Indiana University