Monensin Is a Potent Inducer of Oxidative Stress and Inhibitor of Androgen Signaling Leading to Apoptosis in Prostate Cancer Cells

Abstract

Current treatment options for advanced and hormone refractory prostate cancer are limited and responses to commonly used androgen pathway inhibitors are often unsatisfactory. Our recent results indicated that sodium ionophore monensin is one of the most potent and cancer-specific inhibitors in a systematic sensitivity testing of most known drugs and drug-like molecules in a panel of prostate cancer cell models. Because monensin has been extensively used in veterinary applications to build muscle mass in cattle, the link to prostate cancer and androgen signaling was particularly interesting. Here, we showed that monensin effects at nanomolar concentrations are linked to induction of apoptosis and potent reduction of androgen receptor mRNA and protein in prostate cancer cells. Monensin also elevated intracellular oxidative stress in prostate cancer cells as evidenced by increased generation of intracellular reactive oxygen species and by induction of a transcriptional profile characteristic of an oxidative stress response. Importantly, the antiproliferative effects of monensin were potentiated by combinatorial treatment with the antiandrogens and antagonized by antioxidant vitamin C. Taken together, our results suggest monensin as a potential well-tolerated, in vivo compatible drug with strong proapoptotic effects in prostate cancer cells, and synergistic effects with antiandrogens. Moreover, our data suggest a general strategy by which the effects of antiandrogens could be enhanced by combinatorial administration with agents that increase oxidative stress in prostate cancer cells. Mol Cancer Ther; 9(12); 3175-85. Ó2010 AACR.

Monensin Inhibits Canonical Wnt Signaling in Human Colorectal Cancer Cells and Suppresses Tumor Growth in Multiple Intestinal Neoplasia Mice

“…Monensin antibacterial and antiparasitic activity is related to the intracellular changes in pH and sodium-potassium balance that can result in cell death (40). Several recent studies have demonstrated that monensin inhibits growth and induces apoptosis of cells derived from renal, prostate, and colon carcinoma (29,41,42). In addition, monensin induced cell-cycle arrest of acute myelogenous leukemia and lymphoma cells (43,44).…”

“…4G). In prostate cancer cells, monensin treatment reduced the amount of androgen receptor mRNA and elevated oxidative stress (29). However, monensin did not increase the levels of reactive oxygen species (ROS) in HEK293 and SW480 cells ( Supplementary Fig.…”

Monensin Induced Oxidative Stress Reduces Prostate Cancer Cell Migration and Cancer Stem Cell Population

“…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 and disulfiram inhibited prostate cancer cell growth by inducing oxidative stress (Iljin et al 2009, Ketola et al 2010. In contrast to disulfiram, monensin induced apoptosis, reduced androgen receptor signalling and showed a synergistic anti-proliferative effect with anti-androgens in prostate cancer cells.…”

“…androgen receptor (AR), ERG and MYC are known to have antioxidative properties in cancer cells (Pinthus et al 2007, Tam et al 2003, Benassi et al 2006, Swanson et al 2011, DeNicola et al 2011. Monensin may sensitize prostate cancer cells to oxidative stress via reducing the expression of these genes (Ketola et al 2010). In addition, many other anti-neoplastic agents such as vinblastine, cisplatin, mitomycin C, doxorubicin, camptothecin, inostamycin, neocarzinostatin, etoposide, arsenic trioxide and nonsteroidal anti-inflammatory drugs are known to mediate their apoptotic effect by inducing oxidative stress (Fang, Nakamura & Iyer 2007, Rigas, Sun 2008, Sun et al 2011.…”

“…In addition, many other anti-neoplastic agents such as vinblastine, cisplatin, mitomycin C, doxorubicin, camptothecin, inostamycin, neocarzinostatin, etoposide, arsenic trioxide and nonsteroidal anti-inflammatory drugs are known to mediate their apoptotic effect by inducing oxidative stress (Fang, Nakamura & Iyer 2007, Rigas, Sun 2008, Sun et al 2011. The increased sensitivity to oxidative stress combined with dependency on antioxidative system may provide a way to selectivity inhibit cancer cell proliferation (Iljin et al 2009, Ketola et al 2010.…”