Abstract
2318
Death from prostate cancer is due to hormonal and chemotherapy resistance. New therapies are needed. We have previously shown that the naturally occurring product, parthenolide, inhibits NFκB and cellular proliferation in vitro. However, it has no single agent activity in in vivo models although it augments the efficacy of the anti-androgen, bicalutamide, and the cytotoxic, docetaxel. Dimethylaminoparthenolide DMAPT is a bioavailable analogue and provides serum concentrations greater than 20µM in mice. Our recent in vitro studies using the androgen independent cell lines, PC-3 and CWR22Rv1, have shown that DMAPT inhibits NFκB DNA binding and proliferation of CWR22Rv1 and PC-3 with IC50’s between 5 and 10μM. Moreover, DMAPT reduces expression of the NFκB target gene TRAF2 in both cell lines as well as induces re-expression of p73 in PC-3 but not in CWR22Rv1. Further, DMAPT results in generation of reactive oxygen species (ROS) with resultant phosphorylation of JNK and cJun. N-acetylcysteine (NAC), blocks DMAPT induced generation of ROS and JNK/cJun activation as well as its anti-proliferative properties . Furthermore, the JNK inhibitor SP600125 blocks the ability of DMAPT to induce JNK activation and partially protects the cells from DMAPT’s anti-cancer activity. To determine whether DMAPT has single agent in vivo activity in prostate cancer cells, athymic nude mice were inoculated subcutaneously with CWR22Rv1 and PC-3 in the flank. Mice were treated by daily oral gavage with solvent (control) or DMAPT at doses ranging from 40 to 100 mg/kg/day as well as 100 mg/kg twice per day. Unlike parthenolide, DMAPT as a single agent decreased the volume of the subcutaneous tumors in a dose dependent manner. In conclusion, DMAPT has a complex mechanism of action that involves both the generation of ROS and inhibition of an oncogenic transcription factor, NF\#312;B. The improved water solubility has resulted in single agent in vivo activity in two androgen independent prostate cancer cell lines.
99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA