Abstract A62: Monensin-induced oxidative stress reduces prostate cancer cell motility and cancer stem cell markers.

Abstract

Abstract Therapeutic options for prostate cancer are limited and treatment responses to currently existing therapies are often unsatisfactory. Thus, there is an urgent need for novel agents to target advanced and metastatic prostate cancer cells. We have recently carried out a chemical-biological high-throughput screening of 4,910 known drugs and drug-like molecules in four prostate cancer cell models and two non-tumorigenic prostate epithelial cell lines to identify prostate cancer cell growth selective inhibitors. Only four compounds, antibiotic ionophore monensin, aldehyde dehydrogenase (ALDH) inhibitor disulfiram, histone deacetylase inhibitor trichostatin A and fungicide thiram inhibited selectively cancer cell growth at nanomolar concentrations. The mechanistic studies indicated that monensin inhibited prostate cancer cell growth by inducing oxidative stress and apoptosis. In addition, monensin reduced androgen receptor signaling, showed a synergistic anti-proliferative effect with anti-androgens as well as reduced the levels of MYC and ERG oncogenes and reduced the activity of ALDH in prostate cancer cells. Moreover, antioxidant vitamin C rescued the monensin induced growth inhibition, indicating that oxidative stress plays a key role in the antineoplastic effect of monensin in cultured prostate cancer cells. Our previous Connectivity Map results indicated that monensin has agonistic effects to NF-κB inactivator and oxidative stress inducer niclosamide. Here, we show that monensin indeed reduced the activity of NF-κB pathway. NF-κB maintains cellular antioxidant defence capacity and its inhibition induces oxidative stress as well as reduces tumorigenesis, metastasis and cancer stem cell potential. Cancer stem cells have a controlled redox balance system including high ALDH and CD44 expression which protect cancer stem cells from oxidative stress. Our results confirmed that monensin reduced the cancer stem cell markers in prostate cancer cells. Moreover, monensin induced epithelial cell differentiation shown as well as reduced motility in cultured prostate cancer cells, suggesting that monensin inhibits prostate tumorigenesis by multiple ways. Furthermore, the steroid profiling indicated that monensin increases the levels of oxidative stress inducing steroids and reduces androgen precursors in cultured prostate cancer cells. In conclusion, our results suggest that impairing the redox control, which has a crucial role in cancer cells enabling survival under high intracellular ROS, is a potent way to target prostate cancer cells and potentially also prostate cancer stem cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A62.