A novel substrate mimetic inhibitor of PKB/Akt inhibits prostate cancer tumor growth in mice by blocking the PKB pathway.
We describe a novel, potent peptide substrate mimetic inhibitor of protein kinase B (PKB/Akt). The compound selectively kills prostate cancer cells, in which PKB is highly activated, but not normal cells, or cancer cells in which PKB is not activated. The inhibitor induces apoptosis and inhibits the phosphorylation of PKB substrates in prostate cancer cell lines and significantly increases the efficacy of chemotherapy agents to induce prostate cancer cell death, when given in combination. In vivo, the inhibitor exhibits a strong antitumor effect in two prostate cancer mouse models. Moreover, treated animals develop significantly less lung metastases compared to untreated ones, and the effect is accompanied by a significant decrease in blood PSA [prostate-specific antigen] levels in treated animals. This compound and its potential analogues may be developed into novel, potent, and safe anticancer agents, both as stand-alone treatment and in combination with other chemotherapy agents.
Litman
Pninit
P
DeveloGen Israel Ltd., Kiryat Weizmann, Building 16, Rehovot, Israel.
Ohne
Osnat
O
Ben-Yaakov
Shirly
S
Shemesh-Darvish
Liron
L
Yechezkel
Tamar
T
Salitra
Yosef
Y
Rubnov
Shai
S
Cohen
Ilana
I
Senderowitz
Hanoch
H
Kidron
Dvora
D
Livnah
Oded
O
Levitzki
Alexander
A
Livnah
Nurit
N
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002788:Cholesterol Esters / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051379:Mice; D008942:Mitoxantrone / Q000494:pharmacology; D008958:Models, Molecular; D009842:Oligopeptides / Q000627:therapeutic use*; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects
D002788:Cholesterol Esters; D004791:Enzyme Inhibitors; D009842:Oligopeptides; C520349:cholesteryl-O-CO-arginyl-prolyl-arginyl-norvalyl-tyrosyl-diaminopimelyl-Hol-NH; D008942:Mitoxantrone; D051057:Proto-Oncogene Proteins c-akt; D017430:Prostate-Specific Antigen