Tirucallic acids are novel pleckstrin homology domain-dependent Akt inhibitors inducing apoptosis in prostate cancer cells

Mol Pharmacol. 2010 Mar;77(3):378-87. doi: 10.1124/mol.109.060475. Epub 2009 Dec 16.


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 short-hairpin RNA 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-alpha-acetoxy-tirucallic acid, and 3-beta-acetoxy-tirucallic acid from the oleogum resin of Boswellia carterii to chemical homogeneity. The acetoxy-derivatives in particular potently inhibited the activities of human recombinant Akt1 and Akt2 and of constitutively active Akt immunoprecipitated from PC-3 cells, whereas inhibitor of nuclear factor-kappaB 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-beta-acetoxy-tirucallic acid did not inhibit the activity of Akt1 lacking the pleckstrin homology domain. In the prostate cancer cell lines investigated, these compounds inhibited the phosphorylation of cellular Akt and the Akt signaling pathways, including glycogen synthase kinase-3beta and BAD phosphorylation, nuclear accumulation of p65, the androgen receptor, beta-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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Binding Sites / drug effects
  • Binding Sites / physiology
  • Blood Proteins / chemistry*
  • Blood Proteins / pharmacology
  • Blood Proteins / therapeutic use
  • Boswellia
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Phosphoproteins / chemistry*
  • Phosphoproteins / pharmacology
  • Phosphoproteins / therapeutic use
  • Plant Extracts / chemistry
  • Plant Extracts / pharmacology
  • Plant Extracts / therapeutic use
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / physiology
  • Triterpenes / chemistry*
  • Triterpenes / pharmacology
  • Triterpenes / therapeutic use
  • Xenograft Model Antitumor Assays / methods


  • 3-oxo-tirucall-8,24-dien-21-oic acid
  • Antineoplastic Agents
  • Blood Proteins
  • Phosphoproteins
  • Plant Extracts
  • Protein Kinase Inhibitors
  • Triterpenes
  • platelet protein P47
  • tirucallane
  • Proto-Oncogene Proteins c-akt