KN-93 inhibits androgen receptor activity and induces cell death irrespective of p53 and Akt status in prostate cancer

• Published in: Cancer biology & therapy Vol. 9; no. 3; pp. 224 - 234
• Main Authors: Rokhlin, Oskar, Guseva, Natalya V., Taghiyev, Agshin F., Glover, Rebecca A., Cohen, Michael B.
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01-02-2010
• Subjects: Androgen Receptor Antagonists; Antibiotics, Antineoplastic - pharmacology; Apoptosis - drug effects; Benzylamines - pharmacology; Binding; Biology; Bioscience; Blotting, Western; Calcium; Cancer; Caspases - metabolism; Cell; Cell Proliferation - drug effects; Cycle; Doxorubicin - pharmacology; Drug Synergism; Electrophoretic Mobility Shift Assay; Flow Cytometry; Humans; Immunoenzyme Techniques; Landes; Luciferases - metabolism; Male; Membrane Potential, Mitochondrial - drug effects; Organogenesis; Phosphatidylinositol 3-Kinases - metabolism; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Protein Kinase Inhibitors - pharmacology; Proteins; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Sulfonamides - pharmacology; TNF-Related Apoptosis-Inducing Ligand - pharmacology; Transfection; Tumor Cells, Cultured; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 1538-4047; 1555-8576
• DOI: 10.4161/cbt.9.3.10747

It has been suggested that the down-regulation of AR expression should be considered the principal strategy for the treatment of hormone-refractory prostate cancer.We have previously shown that inhibition of AR induced PI3K-independent activation of Akt that was mediated by CaMKII. In this study, we found that the CaMKII inhibitor KN-93 has a broader effect on apoptosis than just inhibition of CaMKII: first, KN-93 inhibits AR activity and induces cell death in PCa cells after androgen deprivation when many other drugs fail to kill prostate cancer cells; second, KN-93 inhibits expression of the anti-apoptotic protein Mcl-1 and induces expression of the pro-apoptotic protein PUMA; third, KN-93-mediated cell death is p53-independent; and fourth, KN-93 induces the generation of ROS. The ROS induction allows KN-93 to circumvent the activation of Akt, which occurs in prostate cancer cells under androgen deprivation, since Akt could not inhibit ROS-mediated apoptosis. KN-93 also synergistically induces cell death in combination with low doses of doxorubicin and converts the phenotype of prostate cancer cells from TRAIL-resistant to -sensitive. These data suggest that KN-93 could be used for novel therapeutic approaches when hormonal therapy has failed.