title: Human mesothelioma cells exhibit tumor cell-specific differences in phosphatidylinositol 3-kinase/AKT activity that predict the efficacy of Onconase.
abstract: Malignant mesothelioma is an aggressive cancer with no known cure, which has become a therapeutic challenge. Onconase is one of few chemotherapeutic agents that have been studied in patients with malignant mesothelioma that has the advantage of low toxicity and limited side effects. Here, we evaluate the effect of Onconase on killing of malignant mesothelioma cells and how the phosphatidylinositol 3-kinase/AKT (PI3-K/AKT) survival pathway influences this effect. Our results show that Onconase induces apoptosis in malignant mesothelioma cell lines and that this effect is tumor cell specific. Malignant mesothelioma cell lines with the highest AKT activation, which correlated with the presence of the SV40 large and small T antigen (SV40+), were the most resistant to the drug. Finally, a cooperative effect was observed between small molecule inhibitors of PI3-K and Onconase in the killing of malignant mesothelioma cells. Our results suggest that kinase screening of individual malignant mesotheliomas for endogenous levels of activated PI3-K/AKT may be predictive of the efficacy of Onconase and possibly other chemotherapeutic agents.
authors.affiliation: Department of Pathology, College of Medicine, University of Vermont College of Medicine, 89 Beaumont Avenue, HSRF 215, Burlington, VT 05405, USA.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Ramos-Nino
authors.forename: Giovina
authors.initials: G
authors.lastname: Vianale
authors.forename: Tara
authors.initials: T
authors.lastname: Sabo-Attwood
authors.forename: Luciano
authors.initials: L
authors.lastname: Mutti
authors.forename: Camilo
authors.initials: C
authors.lastname: Porta
authors.forename: Nicholas
authors.initials: N
authors.lastname: Heintz
authors.forename: Brooke T
authors.initials: BT
authors.lastname: Mossman
mesh_terms: D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001344:Autopsy; D020169:Caspases; D004249:DNA Damage / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D020287:In Situ Nick-End Labeling; D008654:Mesothelioma / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D010997:Pleural Neoplasms / Q000378:metabolism* / Q000473:pathology; D011237:Predictive Value of Tests; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D012260:Ribonucleases / Q000494:pharmacology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D000952:Antigens, Polyomavirus Transforming; D000970:Antineoplastic Agents; D020169:Caspases; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012260:Ribonucleases; C494918:AKT1 protein, human; C058703:ranpirnase