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-1α 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.
These findings suggest that BP inhibits proliferation and induces senescence in human glioblastomas by downregulating hTERT expression and consequently telomerase activity. This is the first study to describe regulation of telomerase activity by BP in human glioblastomas.
A retrospective, single-centre, non-randomized study in the management of symptomatic middle cerebral artery (MCA) total occlusion disease to evaluate extracranial-intracranial (EC-IC) bypass as an intervention for patients with atherosclerotic MCA total occlusion, ischemic symptoms (transient ischemic attacks [TIAs]) or poor cerebral haemodynamics who had not responded well to maximal medical treatment was reported. Twenty-three patients were included in the study with the criteria of: having ischemic syndrome, for example, TIA; being associated with atherosclerotic MCA total occlusion disease (compatible with radiological assessment); being failed to respond to optimal medical therapy (e.g. antiplatelet therapy), indicating a repeat TIA or ischemic stroke attack was noted during maximal medical therapy; having poor cerebral perfusion on CT imaging; and having regional cerebrovascular reactivity (rCVR) of <20% when acetazolamide challenge was undergone. Patients had acute ischemic stroke or other major medical co-morbidities were excluded. No patient experienced any recurrent ischemic stroke during a mean follow-up period of 26.5 months except one patient suffered of immediate post-operative ischemic stroke because of the temporal vessel being clipped too long and the hypotension caused by anaesthesia. Post-operative follow-up imaging, which included MRI (MR angiography) and four-vessel digital subtraction angiography revealed a 100% patency of superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis. No significant differences between observation periods (baseline status: 5.46 ± 5.13/85 ± 15; 0.5 month after surgery: 5.18 ± 5.29/85.91 ± 15.46 and 3 months after surgery: 5.09 ± 4.75/85.36 ± 12.27) were found for the neurological evaluations of NIHSS and Barthel Index (both expressed in mean ± SD) in all of the 23 patients. The annual risk of recurrent stroke was 0% after EC-IC bypass. However, studies with a larger scale are warranted to further confirm the effectiveness of EC-IC bypass.
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