Although such compounds inhibit cell proliferation, their effects on cell survival, an important determinant of clinical response, are less distinct. Using a broad panel of myeloma cell lines and primary patient samples, we show that dual PI3K and mTOR inhibition can induce cell death. The effects are most marked

in cells expressing the t(4;14) translocation, whereas t(11; 14) cells are largely resistant. Using specific inhibitors of individual NU7441 concentration pathway components, we show that optimal induction of cell death requires inhibition of both PI3K and mTOR. This is due to a PI3K-independent component of mTOR activation downstream of the MAP kinase pathway. Novel mTOR kinase inhibitors, which block both TORC1 and TORC2 complexes thereby also reducing Akt activity, are less effective than dual PI3K/mTOR inhibitors because of feedback activation of PI3K signalling. Dual PI3K/mTOR inhibitors sensitise t(4; 14) and t(14; 16), but not t(11; 14), expressing cells to the cytotoxic effects of dexamethasone. We have identified a robust cytogenetic biomarker for response to PI3K/mTOR inhibition-these results will inform the design

and prioritisation of clinical studies with novel inhibitors WZB117 in genetic subgroups of myeloma.”
“The role played by endogenous opioids in mediating the reinforcing properties of nicotine is unclear. As with preclinical studies, clinical trials with naloxone, a prototypic opioid receptor antagonist have yielded equivocal

findings with regard to its efficacy in reducing cigarette smoking.

The aim of the present study was to examine the effects of three opioids that exhibit relative selectivity at mu-, kappa- and delta-opioid receptors on nicotine self-administration in male hooded Lister rats.

Graded doses (0.3, 1.0, and 3.0 mg/kg IP) of each opioid agonist or antagonist were tested in different groups of rats repeatedly over three consecutive nicotine intravenous nicotine-self administration (0.03 mg/kg/infusion) sessions. The same treatments were tested in parallel groups Rapamycin purchase of rats trained to respond for food reinforcement.

Naloxone was very effective in attenuating the levels of nicotine self-administered across all doses tested. The selective kappa-opioid receptor agonist U50,488, reduced nicotine self-administration in doses of 1 and 3 mg/kg, while the 0.3 mg/kg dose produced a small increase in nicotine intake. Finally, the specific delta-opioid receptor antagonist, naltrindole did not significantly modify nicotine self-administration behaviour. In contrast, all three opioids failed to modify behaviour maintained by food reinforcement.

These findings suggest endogenous opioids are crucial in mediating the reinforcing effects of nicotine and that the mu-opioid receptor subtype may represent a potential target for selectively reducing nicotine-taking behaviour as part of a pharmacological approach to develop smoking cessation aids.