ABCC4/MRP4: A MYCN-Regulated Transporter and Potential Therapeutic Target in Neuroblastoma.
ABCC4/MRP4: a MYCN-regulated transporter and potential therapeutic target in neuroblastoma.
Filed under: Drug and Alcohol Rehabilitation
Front Oncol. 2012; 2: 178
Huynh T, Norris MD, Haber M, Henderson MJ
Resistance to cytotoxic drugs is thought to be a major cause of treatment failure in childhood neuroblastoma, and members of the ATP-binding cassette (ABC) transporter superfamily may contribute to this phenomenon by active efflux of chemotherapeutic agents from cancer cells. As a member of the C subfamily of ABC transporters, multidrug resistance-associated protein MRP4/ABCC4 has the ability to export a variety of endogenous and exogenous substances across the plasma membrane. In light of its capacity for chemotherapeutic drug efflux, MRP4 has been studied in the context of drug resistance in a number of cancer cell types. However, MRP4 also influences cancer cell biology independently of chemotherapeutic drug exposure, which highlights the potential importance of endogenous MRP4 substrates in cancer biology. Furthermore, MRP4 is a direct transcriptional target of Myc family oncoproteins and expression of this transporter is a powerful independent predictor of clinical outcome in neuroblastoma. Together, these features suggest that inhibition of MRP4 may be an attractive therapeutic approach for neuroblastoma and other cancers that rely on MRP4. In this respect, existing options for MRP4 inhibition are relatively non-selective and thus development of more specific anti-MRP4 compounds should be a major focus of future work in this area.
HubMed – drug
The Entamoeba histolytica serum-inducible transmembrane kinase EhTMKB1-9 is involved in intestinal amebiasis.
Filed under: Drug and Alcohol Rehabilitation
Int J Parasitol Drugs Drug Resist. 2012 Dec; 2: 243-248
Abhyankar MM, Shrimal S, Gilchrist CA, Bhattacharya A, Petri WA
Entamoeba histolytica possesses a family of approximately 100 putative transmembrane kinases (TMKs), indicating that the parasite has an extensive means of environmental sensing. The TMKs have been divided into nine sub-groups based on the sequence composition of their intracellular kinase as well as extracellular cysteine-rich domains. EhTMKB1-9 has been recently shown to be expressed in proliferating trophozoites and induced by serum. Interference with EhTMKB1-9 by antisense RNA knockdown or expression of a truncated protein diminished proliferation, adhesion and cytotoxicity. Here we report the involvement of EhTMKB1-9 in phagocytosis and its virulence function in the formation of amebic colitis. Trophozoites induced to express higher levels of wild type EhTMKB1-9 showed increased capacity for endocytosis. In contrast, cells compromised for the EhTMKB1-9 expression through antisense inhibition showed significantly lower levels of phagocytosis and endocytosis under the experimental conditions. The role of EhTMKB1-9 as a virulence factor was studied using animal models of amebiasis. Trophozoites expressing high levels of mutant protein lacking the kinase domain showed a competitive disadvantage with regard to survival as well as invasive phenotype in the murine model of amebic colitis. The same parasites however, were not compromised in their ability to generate abscess in the gerbil model of invasive liver amebiasis. EhTMKB1-9 is the second member from the “B” group of EhTMKs which seems to be deployed by the parasite during intestinal infection. TMKs are attractive targets for drug development because of their requirement in virulence and proliferation.
HubMed – drug
The role of the cofilin-actin rod stress response in neurodegenerative diseases uncovers potential new drug targets.
Filed under: Drug and Alcohol Rehabilitation
Bioarchitecture. 2012 Nov 1; 2(6): 204-208
Munsie LN, Truant R
The cofilin-actin rod stress response is an actin cytoskeletal dynamic arrest that occurs in cells under a variety of stress conditions. Upon stress, the rapidly activated cofilin saturates actin filaments causing them to bundle into rod structures in either the nucleus or cytoplasm, halting actin polymerization and thus freeing ATP. Importantly, these rods dissociate quickly following relief of the transient stress. The rods form inappropriately in neurons involved in the progression of Alzheimer disease (AD) and we have linked dysfunctional dynamics of the nuclear rod response to Huntington disease (HD). Cofilin levels are also perturbed in Parkinson disease (PD), and profilin, an actin binding protein with opposite action to cofilin, is mutated in Amyotrophic Lateral Sclerosis (ALS). The persistence of the rods post-stress suggests that critical molecular switches to turn this response both on and off are being affected in neurodegeneration. We have recently shown that the cofilin protein is regulated by highly conserved nuclear import and export signals and that these signals are required to be functional for an appropriate rod formation during stress. The ability of cofilin to form rods is required in a cell culture model for cells to be resistant to apoptosis under stress conditions, indicating that a normal cofilin-actin rod response is likely integral to proper cell health in higher order organisms. Here we hypothesize on the potential physiological function of nuclear cofilin-actin rods and why the dysregulation of this response could lead to the selective vulnerability of the most susceptible populations of cells in HD. We further suggest that learning more about this cytoskeletal cell stress response will open up new avenues for drug target discovery in neurodegenerative disorders.
HubMed – drug
Injection Anthrax-a New Outbreak in Heroin Users.
Filed under: Drug and Alcohol Rehabilitation
Dtsch Arztebl Int. 2012 Dec; 109(49): 843-8
Grunow R, Verbeek L, Jacob D, Holzmann T, Birkenfeld G, Wiens D, von Eichel-Streiber L, Grass G, Reischl U
BACKGROUND: Injection anthrax is a rare disease that affects heroin users and is caused by Bacillus anthracis. In 2012, there were four cases in Germany, one of which was fatal, as well as a small number of cases in other European countries, including Denmark, France, and the United Kingdom. Three cases among drug users occurred in Germany in 2009/2010, in the setting of a larger outbreak centered on Scotland, where there were 119 cases. CASE PRESENTATION AND CLINICAL COURSE: We present three cases of injection anthrax, two of which were treated in Regensburg and one in Berlin. One patient died of multi-organ-system failure on the day of admission to the hospital. The others were treated with antibiotics, one of them also with surgical wound debridement. The laboratory diagnosis of injection anthrax is based on the demonstration of the pathogen, generally by culture and/or by polymerase chain reaction, in material removed directly from the patient’s wound. The diagnosis is additionally supported by the detection of specific antibodies. CONCLUSION: Injection anthrax may be viewed either as an independent disease entity or as a special type of cutaneous anthrax with massive edema, necrotizing fasciitis in many cases, and about 30% mortality. It has appeared in recent years among heroin users in various European countries. In patients with suggestive clinical presentation and a history of heroin use, anthrax infection must be suspected early, so that the appropriate diagnostic tests can be performed without delay. Timely treatment can be life-saving. It is therefore important that physicians-and the individuals at risk-should be well-informed about this disease.
HubMed – drug
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