title: Triciribine Phosphate Monohydrate, an AKT Inhibitor, Enhances Gemcitabine Activity in Pancreatic Cancer Cells.
abstract: BACKGROUND
  Pancreatic cancer is a highly lethal cancer due to early metastasis and resistance to current chemotherapeutic agents. Abnormal protein kinase B (AKT) activation is an important mechanism of chemoresistance to gemcitabine, the most widely used agent in pancreatic cancer.
  
  
  METHODS
  In the study, we tested the hypothesis that combining an AKT inhibitor with gemcitabine would augment anti-tumor activity. We treated human pancreatic cancer MiaPaCa-2 cells with gemcitabine and the AKT inhibitor triciribine, alone and in combination, and evaluated treatment effects using trypan blue assay, 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium (MTT) assay, and cell death enzyme-linked immunosorbant assay. Colorimetric data of MTT assay were computationally analyzed for synergism of the combination therapy by CalcuSyn2 (Biosoft, Great Shelford, Cambridge, UK).
  
  
  RESULTS
  Both gemcitabine and triciribine inhibited cell growth in a dose-dependent manner. Triciribine synergistically enhanced the cytotoxic activity of gemcitabine. The combination index (CI) provides the synergistic, additive, or antagonistic effects of the two-drug combination. CI at the 50% effective dose at 1:500 ratio of gemcitabine to triciribine was 0.74, indicating the synergistic effect of the drugs. The combination treatment with the non-apoptotic dose of each agent distinctly induced apoptosis, with gemcitabine in combination with triciribine, synergistically inhibiting pancreatic cancer cell growth and inducing apoptosis.
  
  
  CONCLUSIONS
  These findings support the use of triciribine to overcome activated AKT-mediated resistance of pancreatic cancer to gemcitabine.
authors.affiliation: Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A. Richard.Kim@moffitt.org.
authors.forename: Richard
authors.initials: R
authors.lastname: Kim
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, St. Luke's International Hospital, Tokyo, Japan.
authors.forename: Teruo
authors.initials: T
authors.lastname: Yamauchi
authors.affiliation: Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A. Department of Oncologic Sciences, University of South Florida, Tampa, FL, U.S.A. Department of Molecular Medicine, University of South Florida, Tampa, FL, U.S.A.
authors.forename: Kazim
authors.initials: K
authors.lastname: Husain
authors.affiliation: Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A. Department of Oncologic Sciences, University of South Florida, Tampa, FL, U.S.A. Department of Molecular Medicine, University of South Florida, Tampa, FL, U.S.A.
authors.forename: Said
authors.initials: S
authors.lastname: Sebti
authors.affiliation: Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A.
authors.forename: Mokenge
authors.initials: M
authors.lastname: Malafa
mesh_terms: D000073:Acenaphthenes / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology / Q000627:therapeutic use*; D013194:Staining and Labeling; D014343:Trypan Blue / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D000073:Acenaphthenes; D047428:Protein Kinase Inhibitors; D012265:Ribonucleotides; D003841:Deoxycytidine; C014205:triciribine phosphate; D051057:Proto-Oncogene Proteins c-akt; D014343:Trypan Blue; D000093542:Gemcitabine
keywords: AKT inhibitor; gemcitabine; pancreatic cancer