Addiction Rehab: Novel Hsp90 Inhibitor NVP-AUY922 Radiosensitizes Prostate Cancer Cells.

Novel Hsp90 inhibitor NVP-AUY922 radiosensitizes prostate cancer cells.

Filed under: Addiction Rehab

Cancer Biol Ther. 2013 Jan 28; 14(4):
Gandhi N, Wild AT, Chettiar ST, Aziz K, Kato Y, Gajula RP, Williams RD, Cades JA, Annadanam A, Song D, Zhang Y, Hales RK, Herman JM, Armour E, Deweese TL, Schaeffer EM, Tran PT

Outcomes for poor-risk localized prostate cancers treated with radiation are still insufficient. Targeting the “non-oncogene” addiction or stress response machinery is an appealing strategy for cancer therapeutics. Heat-shock-protein-90 (Hsp90), an integral member of this machinery, is a molecular chaperone required for energy-driven stabilization and selective degradation of misfolded “client” proteins that is commonly overexpressed in tumor cells. Hsp90 client proteins include critical components of pathways implicated in prostate cancer cell survival and radioresistance, such as androgen receptor signaling and the PI3K-Akt-mTOR pathway. We examined the effects of a novel non-geldanamycin Hsp90 inhibitor, AUY922, combined with radiation (RT) on two prostate cancer cell lines, Myc-CaP and PC3, using in vitro assays for clonogenic survival, apoptosis, cell cycle distribution, ?-H2AX foci kinetics and client protein expression in pathways important for prostate cancer survival and radioresistance. We then evaluated tumor growth delay and effects of the combined treatment (RT-AUY922) on the PI3K-Akt-mTOR and AR pathways in a hind-flank tumor graft model. We observed that AUY922 caused supra-additive radiosensitization in both cell lines at low nanomolar doses with enhancement ratios between 1.4-1.7 (p < 0.01). RT-AUY922 increased apoptotic cell death compared with either therapy alone, induced G 2-M arrest and produced marked changes in client protein expression. These results were confirmed in vivo, where RT-AUY922 combination therapy produced supra-additive tumor growth delay compared with either therapy by itself in Myc-CaP and PC3 tumor grafts (both p < 0.0001). Our data suggest that combined RT-AUY922 therapy exhibits promising activity against prostate cancer cells, which should be investigated in clinical studies. HubMed – addiction


Reduced presynaptic dopamine activity in adolescent dorsal striatum.

Filed under: Addiction Rehab

Neuropsychopharmacology. 2013 Jan 28;
Matthews M, Bondi C, Torres G, Moghaddam B

Adolescence coincides with symptomatic onset of several psychiatric illnesses including schizophrenia and addiction. Excess limbic dopamine activity has been implicated in these vulnerabilities. We combined molecular and dynamic indices of dopamine neurotransmission to assess dopamine function in adolescent rats in two functionally distinct striatal subregions: nucleus accumbens (NAc), and dorsal striatum (DS). In adolescents, we find an overall reduction in dopamine availability selective to the DS. Dopamine release in the DS, but not NAc, was less responsive to amphetamine in adolescents compared in adults. The dopamine transporter (DAT) inhibitor nomifensine similarly inhibited basal and amphetamine-induced dopamine release in both regions of both age groups, suggesting that the reduced effectiveness of amphetamine is not due to differences in DAT function. Furthermore, DAT and vesicular monoamine transporter-2 expression were similar in the DS and NAc of adolescent rats. In contrast, expression of tyrosine hydroxylase (TH) was reduced in the DS, but not the NAc, of adolescents compared to adults. Behaviorally, adolescents were less sensitive to amphetamine but more sensitive to a TH inhibitor. These data indicate that, in contrast to the general notion that dopamine is hyperactive in adolescents, there is diminished presynaptic dopamine activity in adolescents that is selective to the DS and may result from attenuated TH activity. Given recent reports of altered dopamine activity in associative/dorsal striatum of individuals at clinical high risk for psychosis, our data further support the idea that dorsal, as opposed to ventral, regions of the striatum are a locus of vulnerability for psychosis.Neuropsychopharmacology accepted article preview online, 28 January 2013;. doi:10.1038/npp.2013.32.
HubMed – addiction


Impact of an electronic cigarette on smoking reduction and cessation in schizophrenic smokers: a prospective 12-month pilot study.

Filed under: Addiction Rehab

Int J Environ Res Public Health. 2013; 10(2): 446-61
Caponnetto P, Auditore R, Russo C, Cappello GC, Polosa R

Background: Cigarette smoking is a tough addiction to break. This dependence is the most common dual diagnosis for individuals with schizophrenia. Currently three effective drugs are approved for smoking cessation: nicotine replacement therapy (NRT), varenicline and bupropion. However, some serious side effects of varenicline have been reported, including depression, suicidal thoughts, and suicide. The use of bupropion also has side effects. It should not be used by people who have epilepsy or any condition that lowers the seizure threshold, nor by people who take a specific class of drugs called monoamine oxidase inhibitors. Hence, there are pharmacodynamic reason to believe they could precipitate or exacerbate psychosis. For its capacity to deliver nicotine and provide a coping mechanism for conditioned smoking cues by replacing some of the rituals associated with smoking gestures, electronic-cigarettes may reduce nicotine withdrawal symptoms without serious side effects. Our recent work with ECs in healthy smokers not intending to quit consistently show surprisingly high success rates. We hypothesised that these positive findings could be replicated in difficult patients with schizophrenia This tool may help smokers with schizophrenia remain abstinent during their quitting attempts or to reduce cigarette consumption. Efficacy and safety of these devices in long-term smoking cessation and/or smoking reduction studies have never been investigated for this special population. Methods: In this study we monitored possible modifications in smoking habits of 14 smokers (not intending to quit) with schizophrenia experimenting with the “Categoria” e-Cigarette with a focus on smoking reduction and smoking abstinence. Study participants were invited to attend six study visits: at baseline, week-4, week-8, week-12 week-24 and week 52. Product use, number of cigarettes smoked, carbon monoxide in exhaled breath (eCO) and positive and negative symptoms of schizophrenia levels were measured at each visit. Smoking reduction and abstinence rates were calculated. Adverse events were also reviewed. Results: Sustained 50% reduction in the number of cig/day at week-52 was shown in 7/14 (50%) participants; their median of 30 cig/day decreasing significantly to 15 cig/day (p = 0.018). Sustained smoking abstinence at week-52 was observed in 2/14 (14.3%) participants. Combined sustained 50% reduction and smoking abstinence was shown in 9/14 (64.3%) participants. Nausea was observed in 2/14 (14.4%) of participants, throat irritation in 2/14 (14.4%) of participants, headache in 2/14 (14.4%) of participants , and dry cough in 4/14 (28.6%) of participants. However, these adverse events diminished substantially by week-24. Overall, one to two cartridges/day were used throughout the study. Positive and negative symptoms of schizophrenia are not increased after smoking reduction/cessation in patients using e-cigarettes. Conclusions: We have shown for the first time that the use of e-cigarette substantially decreased cigarette consumption without causing significant side effects in chronic schizophrenic patients who smoke not intending to quit. This was achieved without negative impacts on the symptoms of schizophrenia as assessed by SAPS and SANS symptoms scales.
HubMed – addiction


PIAS? Enhanced SUMO-2 Modification of Nurr1 Activation-Function-1 Domain Limits Nurr1 Transcriptional Synergy.

Filed under: Addiction Rehab

PLoS One. 2013; 8(1): e55035
Arredondo C, Orellana M, Vecchiola A, Pereira LA, Galdames L, Andrés ME

Nurr1 (NR4A2) is a transcription factor that belongs to the orphan NR4A group of the nuclear receptor superfamily. Nurr1 plays key roles in the origin and maintenance of midbrain dopamine neurons, and peripheral inflammatory processes. PIAS?, a SUMO-E3 ligase, represses Nurr1 transcriptional activity. We report that Nurr1 is SUMOylated by SUMO-2 in the lysine 91 located in the transcriptional activation function 1 domain of Nurr1. Nurr1 SUMOylation by SUMO-2 is markedly facilitated by overexpressing wild type PIAS?, but not by a mutant form of PIAS? lacking its first LXXLL motif (PIAS?mut1). This PIAS?mut1 is also unable to interact with Nurr1 and to repress Nurr1 transcriptional activity. Interestingly, the mutant PIAS?C342A that lacks SUMO ligase activity is still able to significantly repress Nurr1-dependent transcriptional activity, but not to enhance Nurr1 SUMOylation. A SUMOylation-deficient Nurr1 mutant displays higher transcriptional activity than the wild type Nurr1 only in promoters harboring more than one Nurr1 response element. Furthermore, lysine 91, the major target of Nurr1 SUMOylation is contained in a canonical synergy control motif, indicating that SUMO-2 posttranslational modification of Nurr1 regulates its transcriptional synergy in complex promoters. In conclusion, PIAS? can exert two types of negative regulations over Nurr1. On one hand, PIAS? limits Nurr1 transactivation in complex promoters by SUMOylating its lysine 91. On the other hand, PIAS? fully represses Nurr1 transactivation through a direct interaction, independently of its E3-ligase activity.
HubMed – addiction



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