BACKGROUND/AIMS: Control of apoptosis in autosomal dominant polycystic kidney disease (ADPKD) and in at least some cancers is likely regulated by the endogenous cyclin kinase inhibitor p21, levels of this protein being decreased in ADPKD and increased in many malignancies. The cyclin kinase inhibitor roscovitine has shown efficacy in treatment of murine PKD. We asked how a single agent can be efficacious in both PKD and cancer. METHODS: Renal tubular epithelial cells were incubated at diverse roscovitine concentrations; apoptosis and senescence were measured. Subsequently, levels of pro- and antiapoptotic proteins were evaluated. RESULTS: Renal tubular epithelial cells exposed to 'low' concentrations of roscovitine showed minimal apoptosis in association with markedly increased levels of the antiapoptotic protein p21, and these cells became senescent. Conversely, cells exposed to 'high' levels of roscovitine became apoptotic. The mechanism of antiapoptosis and senescence with 'low'-dose roscovitine involves augmentation of the antiapoptotic proteins. CONCLUSIONS: Data in this study provide a mechanistic explanation of how roscovitine is effective in PKD, and suggest that further study of this agent should focus on assessment of dose response. Furthermore, our discovery of senescence induced by a PKD effective drug suggests a new area of therapeutic investigation in this disease. (c) 2008 S. Karger AG, Basel.
BACKGROUND/AIMS: Control of apoptosis in autosomal dominant polycystic kidney disease (ADPKD) and in at least some cancers is likely regulated by the endogenous cyclin kinase inhibitor p21, levels of this protein being decreased in ADPKD and increased in many malignancies. The cyclin kinase inhibitor roscovitine has shown efficacy in treatment of murinePKD. We asked how a single agent can be efficacious in both PKD and cancer. METHODS: Renal tubular epithelial cells were incubated at diverse roscovitine concentrations; apoptosis and senescence were measured. Subsequently, levels of pro- and antiapoptotic proteins were evaluated. RESULTS: Renal tubular epithelial cells exposed to 'low' concentrations of roscovitine showed minimal apoptosis in association with markedly increased levels of the antiapoptotic protein p21, and these cells became senescent. Conversely, cells exposed to 'high' levels of roscovitine became apoptotic. The mechanism of antiapoptosis and senescence with 'low'-dose roscovitine involves augmentation of the antiapoptotic proteins. CONCLUSIONS: Data in this study provide a mechanistic explanation of how roscovitine is effective in PKD, and suggest that further study of this agent should focus on assessment of dose response. Furthermore, our discovery of senescence induced by a PKD effective drug suggests a new area of therapeutic investigation in this disease. (c) 2008 S. Karger AG, Basel.
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