PT  - JOURNAL ARTICLE
AU  - Aydee Constanza Estrada
AU  - Tatiana Syrovets
AU  - Kai Pitterle
AU  - Oleg Lunov
AU  - Berthold Buchele
AU  - Judith Schimana-Pfeifer
AU  - Thomas Schmidt
AU  - Samy A.F. Morad
AU  - Thomas Simmet
TI  - Tirucallic Acids Are Novel Pleckstrin Homology Domain-Dependent Akt Inhibitors Inducing Apoptosis in Prostate Cancer Cells
AID  - 10.1124/mol.109.060475
DP  - 2009 Jan 01
TA  - Molecular Pharmacology
PG  - mol.109.060475
4099  - http://molpharm.aspetjournals.org/content/early/2009/12/16/mol.109.060475.short
4100  - http://molpharm.aspetjournals.org/content/early/2009/12/16/mol.109.060475.full
AB  - Activation of the serine/threonine kinase Akt is associated with aggressive clinical behavior of prostate cancer. We found that the human prostate cancer cell lines LNCaP and PC-3 express predominantly Akt1 and Akt2. Selective down-regulation of Akt1, but not Akt2 by shRNA reduced the viability of prostate cancer cells. In addition, structurally different Akt inhibitors were cytotoxic for the prostate cancer cells confirming that the Akt pathway is indispensable for their viability. We have purified the tetracyclic triterpenoids 3-oxo-tirucallic acid, 3-α-acetoxy-tirucallic acid and 3-β-acetoxy-tirucallic acid from the oleogum resin of Boswellia carterii to chemical homogeneity. Specifically the acetoxy-derivatives potently inhibited the activities of human recombinant Akt1, Akt2 and of constitutively active Akt immunoprecipitated from PC-3 cells, whereas IκB kinases remained unaffected. Docking data indicated that these tetracyclic triterpenoids form hydrogen bonds within the phosphatidylinositol binding pocket of the Akt pleckstrin homology domain. Accordingly, 3-β-acetoxy-tirucallic acid did not inhibit the activity of Akt1 lacking the PH domain. In the prostate cancer cell lines investigated, these compounds inhibited the phosphorylation of cellular Akt and the Akt signaling pathways including GSK-3β and BAD phosphorylation, nuclear accumulation of p65, the androgen receptor, β-catenin, and c-myc. These events culminated in the induction of apoptosis in prostate cancer, but not in nontumorigenic cells. The tirucallic acid derivatives inhibited proliferation and induced apoptosis in tumors xenografted onto chick chorioallantoic membranes and decreased the growth of pre-established prostate tumors in nude mice without overt systemic toxicity. Thus, tirucallic acid derivatives represent a new class of Akt inhibitors with antitumor properties.The American Society for Pharmacology and Experimental Therapeutics