title: A novel substrate mimetic inhibitor of PKB/Akt inhibits prostate cancer tumor growth in mice by blocking the PKB pathway.
abstract: 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.
authors.affiliation: DeveloGen Israel Ltd., Kiryat Weizmann, Building 16, Rehovot, Israel.
authors.forename: Pninit
authors.initials: P
authors.lastname: Litman
authors.forename: Osnat
authors.initials: O
authors.lastname: Ohne
authors.forename: Shirly
authors.initials: S
authors.lastname: Ben-Yaakov
authors.forename: Liron
authors.initials: L
authors.lastname: Shemesh-Darvish
authors.forename: Tamar
authors.initials: T
authors.lastname: Yechezkel
authors.forename: Yosef
authors.initials: Y
authors.lastname: Salitra
authors.forename: Shai
authors.initials: S
authors.lastname: Rubnov
authors.forename: Ilana
authors.initials: I
authors.lastname: Cohen
authors.forename: Hanoch
authors.initials: H
authors.lastname: Senderowitz
authors.forename: Dvora
authors.initials: D
authors.lastname: Kidron
authors.forename: Oded
authors.initials: O
authors.lastname: Livnah
authors.forename: Alexander
authors.initials: A
authors.lastname: Levitzki
authors.forename: Nurit
authors.initials: N
authors.lastname: Livnah
mesh_terms: 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
chemical_list: 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