title: AKT inhibition by triciribine alone or as combination therapy for growth             control of gastroenteropancreatic neuroendocrine tumors.
abstract: Up-regulation of phosphatidylinositol-3-kinase (PI3K)-AKT signaling facilitates             tumor cell growth and inhibits cell demise. The AKT-pathway also plays an important             role in cytostatic therapy resistance and response to hypoxia and angiogenesis.             Using real-time cell proliferation assay we examined the potency of triciribine             in three distinct neuroendocrine gastrointestinal tumor cell lines. Also we investigated             triciribine's induction of apoptosis and effects on a broad range of cancer-associated             gene products. Furthermore, we characterized the role of PTEN as a possible predictor             of sensitivity to triciribine in GEP-NETs. We also looked for additive anti-neoplastic             effects of triciribine when combined with conventional cytostatic drugs or other             targeted drugs, affecting different molecules of the PI3K-AKT-pathway and we assessed             the potency of triciribine to inhibit tumor growth in vivo, by using the chick             chorioallantoic membrane assay. Treatment of insulinoma (CM) or gut neuroendocrine             tumor cells (STC-1) with triciribine significantly reduced tumor cell growth by             59% and 65%, respectively. By contrast, the highly expressing PTEN carcinoid cell             line BON did not respond, even at higher doses. Combinations of triciribine with             classic cytostatic drugs as well as drugs targeting other molecules of the PI3K-AKT-pathway             led to synergistic anti-proliferative effects. Additional in vivo-evaluations             confirmed the anti-neoplastic potency of triciribine. Thus, our data show that             inhibition the AKT-pathway potently reduces the growth of GEP-NET cells alone             or in combination therapies. AKT inhibition may provide a rationale for future             evaluations.
authors.affiliation: Institute of Physiology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Christoph R
authors.initials: CR
authors.lastname: Gloesenkamp
authors.forename: Bianca
authors.initials: B
authors.lastname: Nitzsche
authors.forename: Matthias
authors.initials: M
authors.lastname: Ocker
authors.forename: Pietro
authors.initials: P
authors.lastname: Di Fazio
authors.forename: Karl
authors.initials: K
authors.lastname: Quint
authors.forename: Björn
authors.initials: B
authors.lastname: Hoffmann
authors.forename: Hans
authors.initials: H
authors.lastname: Scherübl
authors.forename: Michael
authors.initials: M
authors.lastname: Höpfner
mesh_terms: D000375:Aging / Q000187:drug effects / Q000235:genetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007340:Insulinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012263:Ribonucleosides / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D012263:Ribonucleosides; D019938:Cyclin D1; C023764:triciribine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human