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

• DOI: 10.4161/cbt.9.3.10747
• Publication Date: 2010-05-24T20:29:34Z
• Authors: Oskar Rokhlin; Natalya V. Guseva; Agshin F. Taghiyev; Rebecca A. Glover; Michael B. Cohen
• Keywords: Male; Membrane Potential, Mitochondrial; 0301 basic medicine; Benzylamines; Antibiotics, Antineoplastic; Blotting, Western; Prostatic Neoplasms; Apoptosis; Drug Synergism; Electrophoretic Mobility Shift Assay; Flow Cytometry; 3. Good health; Immunoenzyme Techniques; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; Doxorubicin; Caspases; Androgen Receptor Antagonists; Humans; Luciferases; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Cell Proliferation

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