PI3K inhibition potentiates Bcl-2-dependent apoptosis in renal carcinoma cells.

Inhibitors of PI3-K/Akt are currently being assessed clinically in patients with advanced RCC. Identification of therapeutic strategies that might enhance the efficacy of PI3-K/Akt inhibitors is therefore of great interest. As PI3-K inhibition would be expected to have many pro-apoptotic effects, we hypothesized that there may be unique synergy between PI3-K inhibitors and BH3-mimetics. Towards this end, we assessed the combination of the PI3K inhibitor LY 294002 and the Bcl-2 family inhibitor ABT-737 in RCC cell lines. We found that the combinatorial treatment with these agents led to a significant increase in PARP cleavage and cell death in all RCC cell lines. The synergized cell death was correlated with decreased levels of Mcl-1 and XIAP, and increased levels in Bim, and appears critically dependent upon the activation of caspase 3 and 8. The enhanced lethality observed with the combination also appears dependent upon the regulation of XIAP, Mcl-1 and Bim levels. Our results suggest that the combination of PI3-K inhibitors with BH3-mimetics may be a viable therapeutic strategy in RCC.

Treatment of post-electroconvulsive therapy agitation with dexmedetomidine.

Post-electroconvulsive therapy (ECT) delirium is commonly encountered in practice, occurring in up to 12% of treatments. Although often easily managed nonpharmacologically, more severe or persistent cases are generally treated with benzodiazepines or propofol. We describe a patient who failed to respond adequately to these medications but responded quite favorably to dexmedetomidine, a centrally acting α2 agonist. There is evidence that dexmedetomidine may have unique, "delirium-sparing" properties; this makes it an attractive option for this indication.

The efficacy of the novel dual PI3-kinase/mTOR inhibitor NVP-BEZ235 compared with rapamycin in renal cell carcinoma.

PURPOSE: Inhibitors of TORC1 have been shown to be active in patients with metastatic renal cell carcinoma (RCC). As the phosphatidylinositol 3-kinase (PI3K) pathway activates numerous other kinases, transcription factors, and proteins associated with cell growth and survival besides mammalian target of rapamycin (mTOR), disruption of this pathway upstream of mTOR may be more effective than inhibition of TORC1 alone. EXPERIMENTAL DESIGN: To investigate this possibility, the dual PI3K/mTOR inhibitor NVP-BEZ235 was compared with rapamycin in RCC cell lines and xenografts generated from 786-O and A498 cells. RESULTS: Treatment of RCC cell lines with NVP-BEZ235 in vitro resulted in the nuclear translocation of p27, greater reduction in tumor cell proliferation, and more complete suppression of Akt, Mnk-1, eIF4E, and 4EBP-1 phosphorylation and cyclin D1 and hypoxia-inducible factor 2alpha (HIF2alpha) expression than that achieved with rapamycin. The reduction of HIF2alpha levels correlated with reduced HIF activity as determined by luciferase assay. NVP-BEZ235 induced growth arrest in both the 786-O and A498 xenografts that was associated with inhibition of Akt and S6 phosphorylation as well as the induction of apoptosis and reduction in markers of tumor cell proliferation. In contrast, rapamycin induced only minimal growth retardation. CONCLUSION: Dual inhibition of PI3K/mTOR with NVP-BEZ235 induced growth arrest in RCC cell lines both in vitro and in vivo more effectively than inhibition of TORC1 alone. These results provide the rationale for the clinical assessment of agents such as NVP-BEZ235 in patients with advanced RCC.

Neuronal susceptibility to GRIM in Drosophila melanogaster measures the rate of genetic changes that scale to lifespan.

Gene expression in Drosophila melanogaster changes significantly throughout life and some of these changes can be delayed by lowering ambient temperature and also by dietary restriction. These two interventions are known to slow the rate of aging as well as the accumulation of damage. It is unknown, however, whether gene expression changes that occur during development and early adult life make an animal more vulnerable to death. Here we develop a method capable of measuring the rate of programmed genetic changes during young adult life in D. melanogaster and show that these changes can be delayed or accelerated in a manner that is predictive of longevity. We show that temperature shifts and dietary restriction, which slow the rate of aging in D. melanogaster, extend the window of neuronal susceptibility to GRIM over-expression in a way that scales to lifespan. We propose that this susceptibility can be used to test compounds and genetic manipulations that alter the onset of senescence by changing the programmed timing of gene expression that correlates and may be causal to aging.