Peptide Aptamers: Tools to Negatively or Positively Modulate HSPB1(27) Function.

Peptide aptamers: tools to negatively or positively modulate HSPB1(27) function.

Philos Trans R Soc Lond B Biol Sci. 2013; 368(1617): 20120075
Gibert B, Simon S, Dimitrova V, Diaz-Latoud C, Arrigo AP

Human HSP27 (HSPB1) is a molecular chaperone sensor which, through dynamic changes in its phosphorylation and oligomerization, allows cells to adapt to changes in their physiology and/or mount a protective response to injuries. In pathological conditions, the high level of HSPB1 expression can either be beneficial, such as in diseases characterized by cellular degenerations, or be malignant in cancer cells where it promotes tumourigenesis, metastasis and anti-cancer drug resistance. Structural changes allow HSPB1 to interact with specific client protein partners in order to modulate their folding/activity and/or half-life. Therefore, the search is open for therapeutic compounds aimed at either down- or upregulating HSPB1 activity. In this respect, we have previously described two peptide aptamers (PA11 and PA50) that specifically interact with HSPB1 small oligomers and decrease its anti-apoptotic and tumourigenic activities. A novel analysis of the different HSPB1-interacting aptamers that were isolated earlier revealed that one aptamer (PA23) has the intriguing ability to stimulate the protective activity of HSPB1. We show here that this aptamer abolishes the dominant negative effect induced by the R120G mutant of ?B-crystallin (HSPB5) by disrupting its interaction with HSPB1. Hence, developing structure-based interfering strategies could lead to the discovery of HSPB1-based therapeutic drugs. HubMed – drug


Hypoxia induces a phase transition within a kinase signaling network in cancer cells.

Proc Natl Acad Sci U S A. 2013 Mar 25;
Wei W, Shi Q, Remacle F, Qin L, Shackelford DB, Shin YS, Mischel PS, Levine RD, Heath JR

Hypoxia is a near-universal feature of cancer, promoting glycolysis, cellular proliferation, and angiogenesis. The molecular mechanisms of hypoxic signaling have been intensively studied, but the impact of changes in oxygen partial pressure (pO2) on the state of signaling networks is less clear. In a glioblastoma multiforme (GBM) cancer cell model, we examined the response of signaling networks to targeted pathway inhibition between 21% and 1% pO2. We used a microchip technology that facilitates quantification of a panel of functional proteins from statistical numbers of single cells. We find that near 1.5% pO2, the signaling network associated with mammalian target of rapamycin (mTOR) complex 1 (mTORC1)-a critical component of hypoxic signaling and a compelling cancer drug target-is deregulated in a manner such that it will be unresponsive to mTOR kinase inhibitors near 1.5% pO2, but will respond at higher or lower pO2 values. These predictions were validated through experiments on bulk GBM cell line cultures and on neurosphere cultures of a human-origin GBM xenograft tumor. We attempt to understand this behavior through the use of a quantitative version of Le Chatelier’s principle, as well as through a steady-state kinetic model of protein interactions, both of which indicate that hypoxia can influence mTORC1 signaling as a switch. The Le Chatelier approach also indicates that this switch may be thought of as a type of phase transition. Our analysis indicates that certain biologically complex cell behaviors may be understood using fundamental, thermodynamics-motivated principles. HubMed – drug


Key role for a glutathione transferase in multiple-herbicide resistance in grass weeds.

Proc Natl Acad Sci U S A. 2013 Mar 25;
Cummins I, Wortley DJ, Sabbadin F, He Z, Coxon CR, Straker HE, Sellars JD, Knight K, Edwards L, Hughes D, Kaundun SS, Hutchings SJ, Steel PG, Edwards R

Multiple-herbicide resistance (MHR) in black-grass (Alopecurus myosuroides) and annual rye-grass (Lolium rigidum) is a global problem leading to a loss of chemical weed control in cereal crops. Although poorly understood, in common with multiple-drug resistance (MDR) in tumors, MHR is associated with an enhanced ability to detoxify xenobiotics. In humans, MDR is linked to the overexpression of a pi class glutathione transferase (GSTP1), which has both detoxification and signaling functions in promoting drug resistance. In both annual rye-grass and black-grass, MHR was also associated with the increased expression of an evolutionarily distinct plant phi (F) GSTF1 that had a restricted ability to detoxify herbicides. When the black-grass A. myosuroides (Am) AmGSTF1 was expressed in Arabidopsis thaliana, the transgenic plants acquired resistance to multiple herbicides and showed similar changes in their secondary, xenobiotic, and antioxidant metabolism to those determined in MHR weeds. Transcriptome array experiments showed that these changes in biochemistry were not due to changes in gene expression. Rather, AmGSTF1 exerted a direct regulatory control on metabolism that led to an accumulation of protective flavonoids. Further evidence for a key role for this protein in MHR was obtained by showing that the GSTP1- and MDR-inhibiting pharmacophore 4-chloro-7-nitro-benzoxadiazole was also active toward AmGSTF1 and helped restore herbicide control in MHR black-grass. These studies demonstrate a central role for specific GSTFs in MHR in weeds that has parallels with similar roles for unrelated GSTs in MDR in humans and shows their potential as targets for chemical intervention in resistant weed management. HubMed – drug


Current practice of antiarrhythmic drug therapy for prevention of atrial fibrillation in Europe: The European Heart Rhythm Association survey.

Europace. 2013 Apr; 15(4): 478-81
Dagres N, Lewalter T, Lip GY, Pison L, Proclemer A, Blomström-Lundqvist C,

The aim of this survey was to provide insight into current practice regarding the use of antiarrhythmic drugs for atrial fibrillation (AF) among members of the European Heart Rhythm Association research network. Thirty-seven centres responded. Rhythm control was preferred in patients with significant AF-related symptoms by 73% of centres, in all patients after a first detected episode by 59%, and in young patients even if AF was well tolerated by 49% of centres. The most common strategy after successful conversion of the first AF episode was a ‘wait-and-see’ approach without initiation of antiarrhythmic drugs (49%). Conventional ?-blockers were always or sometimes used as first-choice drugs for AF prevention by 76% of centres. Only 11% used dronedarone regularly as a first-choice drug. The diagnostic work-up for exclusion of heart disease prior to initiation of class IC antiarrhythmic drugs was limited. Markers monitored for proarrhythmia risk were QRS duration for class IC drugs (68%) and the QT interval for sotalol and amiodarone (65%). In conclusion, rhythm control is more widely employed than expected. Beta-blockers are widely used for AF prevention in contrast to the limited use of the new drug dronedarone. HubMed – drug