Abstract
It has been suggested that the downregulation 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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Androgen Receptor Antagonists*
-
Antibiotics, Antineoplastic / pharmacology
-
Apoptosis / drug effects*
-
Benzylamines / pharmacology*
-
Blotting, Western
-
Caspases / metabolism
-
Cell Proliferation / drug effects
-
Doxorubicin / pharmacology
-
Drug Synergism
-
Electrophoretic Mobility Shift Assay
-
Flow Cytometry
-
Humans
-
Immunoenzyme Techniques
-
Luciferases / metabolism
-
Male
-
Membrane Potential, Mitochondrial / drug effects
-
Phosphatidylinositol 3-Kinases / metabolism
-
Prostatic Neoplasms / drug therapy
-
Prostatic Neoplasms / metabolism
-
Prostatic Neoplasms / pathology*
-
Protein Kinase Inhibitors / pharmacology
-
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*
Substances
-
AR protein, human
-
Androgen Receptor Antagonists
-
Antibiotics, Antineoplastic
-
Benzylamines
-
Protein Kinase Inhibitors
-
Receptors, Androgen
-
Sulfonamides
-
TNF-Related Apoptosis-Inducing Ligand
-
TP53 protein, human
-
Tumor Suppressor Protein p53
-
KN 93
-
Doxorubicin
-
Luciferases
-
Phosphatidylinositol 3-Kinases
-
Proto-Oncogene Proteins c-akt
-
Caspases