Advanced hormone refractory metastatic prostate cancer is the second leading cause of cancer deaths among US men. As commonly used chemotherapeutic agents have limited success in the treatment of prostate cancer, development of novel agents to prevent its occurrence and progression is urgently needed. Reactive oxygen species (ROS) such as hydrogen peroxide, superoxide, hydroxyl free radical and nitric oxide levels are relatively higher in prostate tumors than in normal tissues. In the past 5 years, direct evidence linking ROS with an increase in tumor development in various tissues including that in the prostate has been reported. It has also been demonstrated that androgen modulates ROS production in androgen dependent prostate cancer cells. Although the exact mechanism of ROS production remains unknown, one possibility may be through the induction of the polyamine catabolic pathway as prostate cells produce a large excess of polyamines. Polyamines catabolize through acetylation by spermidine/spermine acetyltransferase (SSAT) followed by oxidation by acetyl polyamine oxidase (APAO) that produces ROS. Recent DNA microarray analysis and qRT-PCR studies carried out in our laboratory have shown that androgen induces overexpression of the SSAT gene in androgen dependent prostate cancer cells. Our preliminary data showed that pretreatment of androgen dependent LNCaP cells with an APAO inhibitor MDL completely abrogates androgen induced oxidative stress. Here, we propose to develop MDL that specifically reduces oxidative stress in prostate cells as an agent that can prevent occurrence, growth and/or progression of prostate cancer.
Our specific aims are: 1) To establish the ability of MDL pretreatment to block androgen induced oxidative stress in androgen dependent prostate cancer cell lines LapC4 and LNCaP by dichlorofluorescene (DCF) oxidation assay. 2) To determine the ability of MDL to reduce oxidative stress in LNCaP tumor xenografts in nude mouse model using Hydroethidine (HEt) oxidation method. 3) To determine the ability of MDL to prevent growth of LNCaP and LapC4 tumor xenografts in nude mouse. 4) To determine the ability of MDL to prevent spontaneous prostate tumor formation in transgenic adenocarcinoma in mouse prostate (TRAMP) model. A successful completion of these Aims will not only establish MDL as a potential prostate cancer chemopreventive agent that can be further developed for clinical use but should also demonstrate the importance of polyamine catabolic pathway as a valid target for prostate cancer chemoprevention. ? ? ?
| Basu, Hirak S; Thompson, Todd A; Church, Dawn R et al. (2009) A small molecule polyamine oxidase inhibitor blocks androgen-induced oxidative stress and delays prostate cancer progression in the transgenic adenocarcinoma of the mouse prostate model. Cancer Res 69:7689-95 |
