Despite advances in
prostate cancer therapy, dissemination and growth of
metastases results in shortened survival. Here we examined the potential anti-
cancer effect of the NF-κB inhibitor
parthenolide (PTL) and its water soluble analogue dimethylaminoparthenolide (DMAPT) on tumour progression and
metastasis in the TRansgenic
Adenocarcinoma of the Mouse Prostate (TRAMP) model of
prostate cancer. Six-week-old male TRAMP mice received PTL (40 mg/kg in 10%
ethanol/saline), DMAPT (100 mg/kg in sterile water), or vehicle controls by oral gavage thrice weekly until palpable tumour formation. DMAPT treatment slowed normal tumour development in TRAMP mice, extending the time-to-palpable prostate tumour by 20%. PTL did not slow overall tumour development, while the
ethanol/saline vehicle used to administer PTL unexpectedly induced an aggressive metastatic tumour phenotype. Chronic
ethanol/saline vehicle upregulated expression of NF-κB, MMP2,
integrin β1,
collagen IV, and
laminin, and induced vascular basement membrane degradation in primary prostate tumours, as well as increased metastatic spread to the lung and liver. All of these changes were largely prevented by co-administration with PTL. DMAPT (in water) reduced
metastasis to below that of water-control. These data suggest that DMAPT has the potential to be used as a
cancer preventive and anti-metastatic
therapy for
prostate cancer. Although low levels of
ethanol consumption have not been shown to strongly correlate with
prostate cancer epidemiology, these results would support a potential effect of chronic low dose
ethanol on
metastasis and the TRAMP model provides a useful system in which to further explore the mechanisms involved.