title: The Akt inhibitor KP372-1 suppresses Akt activity and cell proliferation and induces apoptosis in thyroid cancer cells.
abstract: The phosphatidylinositol 3' kinase (PI3K)/phosphatase and tensin homologue deleted on chromosome ten/Akt pathway, which is a critical regulator of cell proliferation and survival, is mutated or activated in a wide variety of cancers. Akt appears to be a key central node in this pathway and thus is an attractive target for targeted molecular therapy. We demonstrated that Akt is highly phosphorylated in thyroid cancer cell lines and human thyroid cancer specimens, and hypothesised that KP372-1, an Akt inhibitor, would block signalling through the PI3K pathway and inhibit cell proliferation while inducing apoptosis of thyroid cancer cells. KP372-1 blocked signalling downstream of Akt in thyroid tumour cells, leading to inhibition of cell proliferation and increased apoptosis. As thyroid cancer consistently expresses phosphorylated Akt and KP372-1 effectively blocks Akt signalling, further preclinical evaluation of this compound for treatment of thyroid cancer is warranted.
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: M
authors.initials: M
authors.lastname: Mandal
authors.forename: S
authors.initials: S
authors.lastname: Kim
authors.forename: M N
authors.initials: MN
authors.lastname: Younes
authors.forename: S A
authors.initials: SA
authors.lastname: Jasser
authors.forename: A K
authors.initials: AK
authors.lastname: El-Naggar
authors.forename: G B
authors.initials: GB
authors.lastname: Mills
authors.forename: J N
authors.initials: JN
authors.lastname: Myers
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D004249:DNA Damage; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D013777:Tetrazoles / Q000494:pharmacology*; D013964:Thyroid Neoplasms / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D006576:Heterocyclic Compounds, 4 or More Rings; C501199:KP372-1; D011518:Proto-Oncogene Proteins; D013777:Tetrazoles; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt