title: PF573,228 inhibits vascular tumor cell growth, migration as well as angiogenesis, induces apoptosis and abrogates PRAS40 and S6RP phosphorylation.
abstract: PF573,228 is a compound that targets focal adhesion kinase (FAK), a non-receptor protein kinase, which is over-expressed in various tumors. The aim of this study was to evaluate the effects of PF573,228 on the cells derived from mouse vascular tumors, namely, endothelioma cells. The treatment of endothelioma cells with PF573,228 reduced their growth with an IC50 of approximately 4.6 μmol L-1 and inhibited cell migration with an IC50 of about 0.01 μmol L-1. Microscopic studies revealed morphological attributes of apoptosis. These observations were confirmed by ELISA, which showed increased caspase-3 activity. PF573,228 also inhibited angiogenesis in a dose-dependent manner, with an IC50 of approximately 3.7 μmol L-1, and abrogated the phosphorylation of cell survival proteins, proline-rich Akt substrate (PRAS40) and S6 ribosomal protein (S6RP). Array data further revealed that PF573,228 induced caspase-3 activation, thus promoting apoptosis. Since all the processes inhibited by PF573,228 provide important support to tumor survival and progression, the drug may have a potential role in the treatment of vascular tumors.
authors.forename: Peace
authors.initials: P
authors.lastname: Mabeta
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006390:Hemangioendothelioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D015363:Quinolones / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D038601:Ribosomal Protein S6 / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology*; D046509:Tissue Culture Techniques
chemical_list: C521108:6-(4-(3-(methylsulfonyl)benzylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3,4-dihydroquinolin-2(1H)-one; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D015363:Quinolones; D038601:Ribosomal Protein S6; D013450:Sulfones; C508191:proline-rich Akt substrate, 40 kDa protein, mouse; C448579:ribosomal protein S6, mouse; D051416:Focal Adhesion Protein-Tyrosine Kinases