Xanthohumol Impairs Human Prostate Cancer Cell Growth and Invasion and Diminishes the Incidence and Progression of Advanced Tumors in TRAMP Mice

Roberta Venè,Roberto Benelli,Simonetta Astigiano,Simona Minghelli,Francesca Tosetti,Nicoletta Ferrari

doi:10.2119/molmed.2012.00174

Abstract

Despite recent advances in understanding the biological basis of prostate cancer, management of the disease, especially in the phase resistant to androgen ablation, remains a significant challenge. The long latency and high incidence of prostate carcinogenesis provides the opportunity to intervene with chemoprevention to prevent or eradicate prostate malignancies. In this study, we have used human hormone-resistant prostate cancer cells, DU145 and PC3, as an in vitro model to assess the efficacy of xanthohumol (XN) against cell growth, motility and invasion. We observed that treatment of prostate cancer cells with low micromolar doses of XN inhibits proliferation and modulates focal adhesion kinase (FAK) and AKT phosphorylation leading to reduced cell migration and invasion. Oxidative stress by increased production of reactive oxygen species (ROS) was associated with these effects. Transgenic adenocarcinoma of the mouse prostate (TRAMP) transgenic mice were used as an in vivo model of prostate adenocarcinoma. Oral gavage of XN, three times per week, beginning at 4 wks of age, induced a decrease in the average weight of the urogenital (UG) tract, delayed advanced tumor progression and inhibited the growth of poorly differentiated prostate carcinoma. The ability of XN to inhibit prostate cancer in vitro and in vivo suggests that XN may be a novel agent for the management of prostate cancer.

Highlights

Prostate cancer (PCa) is a serious health concern in Western countries and is the most common cause of death from cancer in men [1]
We investigated the therapeutic potential of XN on PCa cell lines, irrespective of their p53 and PTEN status, and on the onset and progression of PCa in the transgenic adenocarcinoma of the mouse prostate (TRAMP) transgenic mice model
We found a significant activity both in vitro and in vivo, and we propose that XN might slow the growth of PCa cells via inhibition of the focal adhesion kinase (FAK)/AKT/nuclear factor (NF)-κB pathways

Summary

Introduction

Prostate cancer (PCa) is a serious health concern in Western countries and is the most common cause of death from cancer in men [1]. The molecular biology of PCa and its progression is characterized by aberrant activity of several regulatory pathways within prostate epithelial cells and in the surrounding stromal tissue. One such pathway is the phosphatidylinositol 3-kinase–AKT pathway, which functionally modulates numerous substrates involved in the regulation of cell proliferation/survival, angiogenesis and tissue invasion [3]. All these processes represent hallmarks of cancer, and a burgeoning literature is defining the importance of AKT in human and experimental tumorigenesis. Loss of function of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and AKT activation have been significantly correlated with PCa progression [4]

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Conclusion