A novel substrate mimetic inhibitor of PKB/Akt inhibits prostate cancer tumor growth in mice by blocking the PKB pathway

Pninit Litman, Osnat Ohne, Shirly Ben-Yaakov, Liron Shemesh-Darvish, Tamar Yechezkel, Yosef Salitra, Shai Rubnov, Ilana Cohen, Hanoch Senderowitz, Dvora Kidron, Oded Livnah, Alexander Levitzki, Nurit Livnah

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)4716-4724
Number of pages9
JournalBiochemistry
Volume46
Issue number16
DOIs
StatePublished - 24 Apr 2007
Externally publishedYes

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