Inhibition Akt by tetracyclic triterpenoids induces cell cycle arrest and apoptosis in prostate cancer cells.

Abstract

Akt is a family of kinases controling cell metabolism, proliferation and apoptosis. Akt plays an important role in progression and chemoresistance of human cancer. We analyzed function of Akt in androgen-dependent LNCaP and androgen-independent PC-3 and DU 145 prostate cancer cells. Akt1 and Akt2, but not the Akt3 isoform are expressed and constitutively active in all cell lines. Three structurally different Akt inhibitors exerted cytotoxic effect on prostate cancer cells indicating that the Akt pathway is indispensable for cancer cell proliferation. The oleogum resins from Boswellia species contain a complex mixture of triterpenoids that possess biological activities including antitumor properties. In search for well-tolerated and stable Akt inhibitors, we have isolated several tetracyclic triterpenoids from the oleogum resin of Boswellia carterii and purified them to chemical homogeneity. Triterpenoids potently inhibited the activities of human recombinant Akt1 and Akt2 in in vitro kinase assays. Similarly, the triterpenoids inhibited Akt activity immunoprecipitated from PC-3 cells, but did not affect the activity of immunoprecipitated IKK. The triterpenoids also inhibited the phosphorylation of cellular Akt, b-catenin and glycogen synthase kinase (GSK)-3b, whereas extracellular signal-regulated kinase (ERK)1/2 phosphorylation remained unaffected. In addition, the compounds down-regulated the expression of the crucial cell cycle regulators cyclin D1 and c-myc followed by reduction of phosphorylation of retinoblastoma protein, cell cycle arrest and apoptosis. Thus, the inhibition of Akt activity is sufficient to trigger apoptosis in prostate cancer cells. Tetracyclic triterpenoids inhibiting Akt in chemoresistant human prostate cancer.