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.
Clinical & experimental metastasis. 2018 Jun 23 [Epub ahead of print]
Katherine L Morel, Rebecca J Ormsby, Emma L Solly, Linh N K Tran, Christopher J Sweeney, Sonja Klebe, Nils Cordes, Pamela J Sykes
Molecular Medicine and Pathology, Flinders Centre for Innovation in Cancer, Flinders University and Medical Centre, Bedford Park, Adelaide, SA, Australia. ., Molecular Medicine and Pathology, Flinders Centre for Innovation in Cancer, Flinders University and Medical Centre, Bedford Park, Adelaide, SA, Australia., Dana-Farber Cancer Institute, Harvard University, Boston, MA, USA., Department of Anatomical Pathology, Flinders University and SA Pathology at Flinders Medical Centre, Bedford Park, SA, Australia., OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden; Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany.