Inhibition of protein kinase B/Akt. implications for cancer therapy.
Protein kinase B (PKB, also called Akt) is an important regulator of cell proliferation and survival. Amplification of genes encoding PKB isoforms has been found in several types of human cancers. In addition, mutations in the phosphatase and tensin homolog deleted on chromosome ten (PTEN), one of the most frequently mutated tumor suppressor genes, results in elevated PKB activity. PKB has a wide range of cellular targets, and the oncogenicity of PKB arises from activation of both proliferative and anti-apoptotic signaling. Furthermore, PKB contributes to tumor progression by promoting cell invasiveness and angiogenesis. These observations establish PKB as an attractive target for cancer therapy. A cellular inhibitor of PKB, termed carboxyl-terminal modulator protein, reverts the phenotype of viral akt-transformed cells, suggesting that a specific PKB inhibitor will be useful in the treatment of tumors with elevated PKB activity. Since inhibition of PKB activity induces apoptosis in a range of mammalian cells, a PKB inhibitor may be effective, in combination with other anticancer drugs, for the treatment of tumors with other mutations.
Hill
Michelle M
MM
Friedrich Miescher Institute, Maulbeerstrasse 66, CH-4058, Basel, Switzerland.
Hemmings
Brian A
BA
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001549:Benzamides; D003920:Diabetes Mellitus / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D019311:Staurosporine / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019311:Staurosporine