Cancer Letters. Volume 232, Issue 2 , 8 February 2006, Pages 161-169. Received 23 November 2004; revised 9 January 2005; accepted 12 February 2005. Available online 19 April 2005. [Link]
Xiaojuan Sun, Miklós Gulyás, Anders Hjerpe and Katalin Dobra
Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, F-46, Karolinska University Hospital, S-141 86 Huddinge, Stockholm, Sweden
Malignant mesothelioma is an increasingly common tumor with an almost 100% mortality rate. It is refractory to conventional treatment. We have previously shown with SSH and microarray that the mRNA expression level of proteasome is higher in epithelioid mesothelioma cell lines than in sarcomatoid ones. This study evaluates the differential apoptotic effect of proteasome inhibitors on both of these mesothelioma sub-lines. Proteasome inhibitors show substantial anti-tumor activity in some tumor cells in vitro and in vivo, but the effects on mesothelioma cells has not been studied. The viability of mesothelioma cells was reduced in a dose- and time-dependent manner by the proteasome inhibitors tested; PSI was effective with a low dose, but higher concentrations were needed for calpain inhibitor I. The epithelioid mesothelioma cells are more sensitive to the inhibitors than the sarcomatoid ones, their IC50 after 24 h of treatment with PSI being 4 and 16 μm, respectively. Other mesothelioma cell lines show similar sensitivity. PSI seemed to decrease mesothelioma viability by inducing apoptosis, as verified by cell morphology, Western blotting analysis of caspase 3 cleavage, and flow-cytometric analysis. In conclusion, PSI, a representative agent that reduces viability and induces apoptosis of mesothelioma cells, might be useful in the treatment of patients with mesothelioma, especially of epithelioid phenotype.
Keywords: Mesothelioma cells; Proteasome; Proteasome inhibitors; Apoptosis