Tumor Cycling Hypoxia Induces Chemoresistance in Glioblastoma Multiforme by Upregulating the Expression and Function of ABCB1.

Tumor cycling hypoxia induces chemoresistance in glioblastoma multiforme by upregulating the expression and function of ABCB1.

Filed under: Drug and Alcohol Rehabilitation

Neuro Oncol. 2012 Sep 3;
Chou CW, Wang CC, Wu CP, Lin YJ, Lee YC, Cheng YW, Hsieh CH

Tumor cycling hypoxia is now a well-recognized phenomenon in animal and human solid tumors. However, how tumor cycling hypoxia impacts chemotherapy is unclear. In the present study, we explored the impact and the mechanism of cycling hypoxia on tumor microenvironment-mediated chemoresistance. Hoechst 33342 staining and hypoxia-inducible factor-1 (HIF-1) activation labeling together with immunofluorescence imaging and fluorescence-activated cell sorting were used to isolate hypoxic tumor subpopulations from human glioblastoma xenografts. ABCB1 expression, P-glycoprotein function, and chemosensitivity in tumor cells derived from human glioblastoma xenografts or in vitro cycling hypoxic stress-treated glioblastoma cells were determined using Western blot analysis, drug accumulation and efflux assays, and MTT assay, respectively. ABCB1 expression and P-glycoprotein function were upregulated under cycling hypoxia in glioblastoma cells concomitant with decreased responses to doxorubicin and BCNU. However, ABCB1 knockdown inhibited these effects. Moreover, immunofluorescence imaging and flow cytometric analysis for ABCB1, HIF-1 activation, and Hoechst 3342 in glioblastoma revealed highly localized ABCB1 expression predominantly in potentially cycling hypoxic areas with HIF-1 activation and blood perfusion in the solid tumor microenvironment. The cycling hypoxic tumor cells derived from glioblastoma xenografts exhibited higher ABCB1 expression, P-glycoprotein function, and chemoresistance, compared with chronic hypoxic and normoxic cells. Tumor-bearing mice that received YC-1, an HIF-1? inhibitor, exhibited suppressed tumor microenvironment-induced ABCB1 induction and enhanced survival rate in BCNU chemotherapy. Cycling hypoxia plays a vital role in tumor microenvironment-mediated chemoresistance through the HIF-1-dependent induction of ABCB1. HIF-1 blockade before and concurrent with chemotherapy could suppress cycling hypoxia-induced chemoresistance.
HubMed – drug


Vestibular-mediated synaptic inputs and pathways to sympathetic preganglionicneurons in the neonatal mouse.

Filed under: Drug and Alcohol Rehabilitation

J Physiol. 2012 Sep 3;
Kasumacic N, Glover JC, Perreault MC

To assess when vestibulosympathetic projections become functional postnatally, and to establish a preparation in which vestibulosympathetic circuitry can be characterized more precisely, we used an optical approach to record VIIIth nerve-evoked synaptic inputs to thoracic sympathetic preganglionic neurons (SPNs) in newborn mice. Stimulation of the VIIIth nerve was performed in an isolated brainstem-spinal cord preparation after retrogradely labeling with the fluorescent calcium indicator Calcium Green Dextran Amine (CGDA) the SPNs and the somatic motoneurons (MNs) in the thoracic (T) segments T2, 4, 6, 8, 10 and 12. Synaptically mediated calcium responses could be visualized and recorded in individual SPNs and MNs, and analyzed with respect to latency, temporal pattern, magnitude and synaptic pharmacology. VIIIth nerve stimulation evoked responses in all SPNs and MNs investigated. The SPN responses had onset latencies from 90-200 msec, compared to much shorter latencies in MNs, and were completely abolished by mephenesin, a drug that preferentially reduces polysynaptic over monosynaptic transmission. Bicuculline and picrotoxin but not strychnine increased the magnitudes of the SPN responses without changing the onset latencies, suggesting a convergence of concomitant excitatory and inhibitory synaptic inputs. Lesions strategically placed to test the involvement of direct vestibulospinal pathways versus indirect pathways within the brain stem showed that vestibulosympathetic inputs in the neonate are mediated predominantly, if not exclusively, by the latter. Thus, already at birth, synaptic connections in the vestibulosympathetic reflex are functional and require the involvement of the ventrolateral medulla as in adult mammals.
HubMed – drug


Light-triggered reversible assemblies of azobenzene-containing amphiphilic copolymer with ?-cyclodextrin-modified hollow mesoporous silica nanoparticles for controlled drug release.

Filed under: Drug and Alcohol Rehabilitation

Chem Commun (Camb). 2012 Sep 3;
Mei X, Yang S, Chen D, Li N, Li H, Xu Q, Ge J, Lu J

Hollow mesoporous silica nanoparticles (HMSs) were modified by ?-cyclodextrin via a “click” reaction, an amphiphilic copolymer with a trans-azobenzene structure was then assembled onto ?-cyclodextrin to cover the surface of the HMSs. The prepared nanocomposites can release drugs in a “release-stop-release” manner by converting light irradiation.
HubMed – drug



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SD Northern Hills Drug Court Turns 5 Years Old

Filed under: Drug and Alcohol Rehabilitation

The program allows convicted felons with drug problems to avoid prison if they remain clean and sober for at least a year. They also must complete extensive treatment services, pass frequent drug and alcohol tests and undergo intensive supervision.
Read more on KDLT News


Is Marijuana Addictive? (DEBATE)

Filed under: Drug and Alcohol Rehabilitation

Legalization proponents claim that addiction and other health problems from legal marijuana would be addressed through heavy taxation to pay for prevention and treatment, as well as regulations to keep it away from kids. That has not worked with …
Read more on Huffington Post


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