Drug and Alcohol Rehabilitation: Pharmacology and Anti-Tumor Activity of RWJ67657, a Novel Inhibitor of P38 Mitogen Activated Protein Kinase.

Pharmacology and anti-tumor activity of RWJ67657, a novel inhibitor of p38 mitogen activated protein kinase.

Filed under: Drug and Alcohol Rehabilitation

Am J Cancer Res. 2012; 2(4): 446-58
Antoon JW, Bratton MR, Guillot LM, Wadsworth S, Salvo VA, Elliott S, McLachlan JA, Burow ME

Endocrine therapy resistance is a primary cause of clinical breast cancer treatment failure. The p38 mitogen activated protein kinase (MAPK) signaling pathway is known to promote ligand independent tumor growth and resistance to endocrine therapy. In this study, we investigated the therapeutic potential of the p38 inhibitor RWJ67657 in the treatment of tamoxifen resistant MDA-MB-361 cells. RWJ67657 dose-dependently decreased both basal and stimulated activation of p38 MAPK signaling in this drug resistant cell system. Decreased activation of p38 by RWJ67657 resulted in inhibition of the downstream p38 targets hsp27 and MAPKAPK. Diminished p38 signaling resulted in inhibition of p38-medated gene transcription. Furthermore, pharmacological inhibition of p38 by RWJ67657 decreased biological effects of p38, including ER-mediated gene expression and clonogenic survival in a dose-dependent manner. Animal studies revealed significantly decreased p38 signaling in vivo following exposure to RWJ67657. Treatment with the inhibitor markedly decreased phosphorylation of p38 in MDA-MB-361 tumors, leading to decreased transcription of both Fra-1 and progesterone receptor. Utilizing well-established xenograft tumor models, we demonstrated that RWJ67657 exhibits potent anti-tumor properties. Treatment with RWJ67657 markedly decreased tamoxifen resistant tumor growth, both in the presence and absence of estrogen. Taken together, our findings demonstrate the therapeutic potential of targeting the p38-MAPK signaling cascade in the treatment of endocrine resistant breast cancer.
HubMed – drug


Small Molecule Screening Identifies Regulators of the Transcription Factor ?FosB.

Filed under: Drug and Alcohol Rehabilitation

ACS Chem Neurosci. 2012 Jul 18; 3(7): 546-56
Wang Y, Cesena TI, Ohnishi Y, Burger-Caplan R, Lam V, Kirchhoff PD, Larsen SD, Larsen MJ, Nestler EJ, Rudenko G

?FosB protein accumulates in the striatum in response to chronic administration of drugs of abuse, L-DOPA, or stress, triggering long lasting neural and behavioral changes that underlie aspects of drug addiction, abnormal involuntary movements (dyskinesia), and depression. ?FosB binds AP-1 DNA consensus sequences found in promoters of many genes and can both repress or activate gene transcription. In the striatum, ?FosB is thought to dimerize with JunD to form a functional transcription factor, though strikingly JunD does not accumulate in parallel. One explanation is that ?FosB can recruit different partners, including itself, depending on the neuron type in which it is induced and the chronic stimulus, generating protein complexes with different effects on gene transcription. To develop chemical probes to study ?FosB, a high-throughput screen was carried out to identify small molecules that modulate ?FosB function. Two compounds with low micromolar activity, termed C2 and C6, disrupt the binding of ?FosB to DNA via different mechanisms, and in in vitro assays stimulate ?FosB-mediated transcription. In cocaine-treated mice, C2 significantly elevates mRNA levels of the AMPA glutamate receptor GluR2 subunit with specificity, a known target gene of ?FosB that plays a role in drug addiction and endogenous resilience mechanisms. C2 and C6 show different activities against ?FosB homodimers compared to ?FosB/JunD heterodimers, suggesting that these compounds can be used as probes to study the contribution of different ?FosB-containing complexes on the regulation of gene transcription in biological systems and to assess the utility of ?FosB as a therapeutic target.
HubMed – drug


Exploration of Synthetic Approaches and Pharmacological Evaluation of PNU-69176E and Its Stereoisomer as 5-HT(2C) Receptor Allosteric Modulators.

Filed under: Drug and Alcohol Rehabilitation

ACS Chem Neurosci. 2012 Jul 18; 3(7): 538-45
Ding C, Bremer NM, Smith TD, Seitz PK, Anastasio NC, Cunningham KA, Zhou J

Allosteric modulators of the serotonin (5-HT) 5-HT(2C) receptor (5-HT(2C)R) present a unique drug design strategy to augment the response to endogenous 5-HT in a site- and event-specific manner with great potential as novel central nervous system probes and therapeutics. To date, PNU-69176E is the only reported selective positive allosteric modulator for the 5-HT(2C)R. For the first time, an optimized synthetic route to readily access PNU-69176E (1) and its diastereomer 2 has been established in moderate to good overall yields over 10 steps starting from commercially available picolinic acid. This synthetic approach not only enables a feasible preparation of a sufficient amount of 1 for use as a reference compound for secondary pharmacological studies, but also provides an efficient synthesis of key intermediates to develop novel and simplified 5-HT(2C)R allosteric modulators. Compound 1 and its diastereomer 2 were functionally characterized in Chinese hamster ovary (CHO) cells stably transfected with the 5-HT(2C)R using an intracellular calcium (Ca(i) (2+)) release assay. Compound 1 demonstrated efficacy and potency as an allosteric modulator for the 5-HT(2C)R with no intrinsic agonist activity. Compound 1 did not alter 5-HT-evoked Ca(i) (2+) in CHO cells stably transfected with the highly homologous 5-HT(2A)R. In contrast, the diastereomer 2 did not alter 5-HT-evoked Ca(i) (2+) release in 5-HT(2A)R-CHO or 5-HT(2C)R-CHO cells or exhibit intrinsic agonist activity.
HubMed – drug


Endocannabinoid Enzyme Engineering: Soluble Human Thio-Monoacylglycerol Lipase (sol-S-hMGL).

Filed under: Drug and Alcohol Rehabilitation

ACS Chem Neurosci. 2012 May 16; 3(5): 393-9
Karageorgos I, Zvonok N, Janero DR, Vemuri VK, Shukla V, Wales TE, Engen JR, Makriyannis A

In the mammalian central nervous system, monoacylglycerol lipase (MGL) is principally responsible for inactivating the endocannabinoid signaling lipid 2-arachidonoylglycerol (2-AG) and modulates cannabinoid-1 receptor (CB1R) desensitization and signal intensity. MGL is also a drug target for diseases in which CB1R stimulation may be therapeutic. To inform the design of human MGL (hMGL) inhibitors, we have engineered a Leu(Leu(169);Leu(176))-to-Ser(Ser(169);Ser(176)) double hMGL mutant (sol-hMGL) which exhibited enhanced solubility properties, and we further mutated this variant by substituting its catalytic-triad Ser(122) with Cys (sol-S-hMGL). The hMGL variants hydrolyzed both 2-AG and a fluorogenic reporter substrate with comparable affinities. Our results suggest that the hMGL cysteine mutant maintains the same overall architecture as wild-type hMGL. The results also underscore the superior nucleophilic nature of the reactive catalytic Ser(122) residue as compared to that of Cys(122) in the sol-S-hMGL mutant and suggest that the nucleophilic character of the Cys(122) residue is not commensurately enhanced within the three dimensional architecture of hMGL. The interaction of the sol-hMGL variants with the irreversible inhibitors AM6580 and N-arachidonylmaleimide (NAM) and the reversible inhibitor AM10212 was profiled. LC/MS analysis of tryptic digests from sol-S-hMGL directly demonstrate covalent modification of this variant by NAM and AM6580, consistent with enzyme thiol alkylation and carbamoylation, respectively. These data provide insight into hMGL catalysis, the key role of the nucleophilic character of Ser(122), and the mechanisms underlying hMGL inhibition by different classes of small molecules.
HubMed – drug


Drug counselor charged with having affair with client

Filed under: Drug and Alcohol Rehabilitation

He also instructed her that whenever she called his home and his wife answered, she should say she was an employee at a local drug and alcohol treatment center. According to an online biography, Radey is “an experienced chemical dependency counselor …
Read more on The Sheboygan Press


Why do rehab programs insist young members call themselves addicts or

Filed under: Drug and Alcohol Rehabilitation

Many of these younger folks are only beginning to struggle with addiction to drugs or alcohol. The recovery community requires them to fully take on the addict and alcoholic identity as a part of the acceptance process. But, from what I've seen, by …
Read more on Winnipeg Free Press


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