Molecular Cancer Therapeutics. May 1, 2005; 4:835-842. [Link]

Maria E. Ramos-Nino1, Giovina Vianale2, Tara Sabo-Attwood1, Luciano Mutti3, Camilo Porta4, Nicholas Heintz1 and Brooke T. Mossman1

1 Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont; 2 Department of Oncology and Neuroscience, Sections of Clinical and General Pathology, G. D’Annunzio University, Chieti, Italy; 3 Health Authority 11, Piemonte-IRRCS S. Maugeri Foundation; and 4 Matteo University Hospital, Pavia, Italy


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.