Inhibition of Akt pathways in the treatment of prostate cancer

Abstract

Akt is a serine/threonine kinase mediating multiple intracellular pathways involved in prostate cancer (CaP) biology. Increased understanding of the molecular mechanisms of Akt activation and signaling have led to the development of an increasing number of Akt inhibitors. These biologic agents demonstrate activity against a wide range of cancers in preclinical studies. Clinical studies of Akt inhibition in CaP are in progress, including agents such as celecoxib, perifosine and genistein. How best to integrate Akt inhibitors with standard CaP therapy or select patients most likely to benefit is the subject of ongoing research.

Targeting IκB Kinase β/NF-κB Signaling in Human Prostate Cancer by a Novel IκB Kinase β Inhibitor CmpdA

“…S1A). To test this model, we first employed a pan Akt inhibitor, perifosine, that simultaneously blocks the activity of all three isoforms of Akt (28, 29). PC3 cells were treated with different concentrations of perifosine for 2 hours and phosphorylation of Akt, IKK (both IKKα and IKKβ), S6K (mTOR target), and IκBα and p65 (IKK substrates) was determined by Western blot.…”

The TGF-β, PI3K/Akt and PTEN pathways: established and proposed biochemical integration in prostate cancer

“…Akt-1, -2 and -3 are isoforms of the serine/threonine protein kinase B family [19]. Akt-1 and Akt-2 are expressed in most tissue types and contribute to increased cell proliferation, survival and glucose metabolism [20].…”

Metabolic alterations in cancer cells and therapeutic implications

“…Genistein, celecoxib, and perifosine are pharmacologic agents that target Akt and have been tested for treating prostate cancer[207]. A cell permeable Akt antibody that blocks the catalytic site of AKT is effective in triggering cell death in various cancer cell lines[208].…”