ABSTRACT
BACKGROUND: We have shown that a sodium ionophore monensin inhibits prostate cancer cell growth. A structurally related compound to monensin, salinomycin, was recently identified as a putative cancer stem cell inhibitor. METHODS: The growth inhibitory potential of salinomycin was studied in a panel of prostate cells. To get insights into the mechanism of action, a variety of assays such as gene expression and steroid profiling were performed in salinomycin-exposed prostate cancer cells. RESULTS: Salinomycin inhibited the growth of prostate cancer cells, but did not affect non-malignant prostate epithelial cells. Salinomycin impacted on prostate cancer stem cell functions as evidenced by reduced aldehyde dehydrogenase activity and the fraction of CD44(+) cells. Moreover, salinomycin reduced the expression of MYC, AR and ERG, induced oxidative stress as well as inhibited nuclear factor-κB activity and cell migration. Furthermore, profiling steroid metabolites revealed increased levels of oxidative stress-inducing steroids 7-ketocholesterol and aldosterone and decreased levels of antioxidative steroids progesterone and pregnenolone in salinomycin-exposed prostate cancer cells. CONCLUSION: Our results indicate that salinomycin inhibits prostate cancer cell growth and migration by reducing the expression of key prostate cancer oncogenes, inducing oxidative stress, decreasing the antioxidative capacity and cancer stem cell fraction.
Subject(s)
Cell Division/drug effects , Cell Movement/drug effects , Oxidative Stress/drug effects , Prostatic Neoplasms/pathology , Pyrans/pharmacology , Aldehyde Dehydrogenase/antagonists & inhibitors , Blotting, Western , Cell Line, Tumor , Humans , Male , NF-kappa B/metabolism , Niclosamide/pharmacology , Prostatic Neoplasms/metabolism , Reactive Oxygen Species/metabolism , Receptors, Androgen/drug effects , Receptors, Androgen/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/drug effects , Terfenadine/pharmacologyABSTRACT
The carbonic anhydrase (CA) enzyme family consists of thirteen active isozymes in mammals. The most recently characterized members of this family are cytosolic CA XIII and membrane-bound CA XV. This article describes recent advances in the CA family, especially CA XIII and XV. We have also included catalytic activity data on human CA XIII and mouse CA XV. Additionally, the inhibition constants of acetazolamide toward these isozymes were determined to be k(cat) = 1.5 x 10(5) s(-1), k(cat)/K(M) = 1.1 x 10(7) M(-1) s(-1) and K(I) = 16 nM for human CA XIII and k(cat) = 4.7 x 10(5) s(-1), k(cat)/K(M) = 3.3 x 10(7) M(-1) s(-1) and K(I) = 72 nM for mouse CA XV. Although the activity of CA XIII is the second lowest reported thus far for any of the human CAs, it may have a role in maintaining the acid-base balance in the kidney and the gastrointestinal and reproductive tracts. CA XV is an exceptional enzyme, as it seems to be active in numerous species, such as rodents, birds and fish, but is absent from humans and chimpanzees. Mouse CA XV is a moderately active enzyme, suggesting that it may play a physiological role at least in the kidney. It is likely that other isozymes have substituted for this protein in humans. In addition to the novel data on CA XIII and XV, we present the catalytic activities as well as inhibition constants of acetazolamide for all mammalian CA isozymes in this review.