Influencing cancer metabolism by lifestyle changes is an attractive strategy as - if effective - exercise-induced problems may be less severe than those induced by classical anti-cancer therapies. Pursuing this idea, clinical trials evaluated the benefit of e.g. different diets such as the ketogenic diet, intermittent caloric restriction and physical exercise (PE) in the primary and secondary prevention of different cancer types. PE proved to be beneficial in the context of breast and colon cancer.Glioblastoma has a dismal prognosis, with an average overall survival of about one year despite maximal safe resection, concomitant radiochemotherapy with temozolomide followed by adjuvant temozolomide therapy. Here, we focused on the influence of PE as an isolated and adjuvant treatment in murine GB therapy.PE did not reduce toxic side effects of chemotherapy in mice administered in a dose escalating scheme as shown before for starvation. Although regular treadmill training on its own had no obvious beneficial effects, its combination with temozolomide was beneficial in the treatment of glioblastoma-bearing mice. As PE might partly act through the induction of reactive oxygen species, dihydroartemisinin - an approved anti-malarial drug which induces oxidative stress in glioma cells - was further evaluated in vitro and in vivo. Dihydroartemisinin showed anti-glioma activity by promoting autophagy, reduced the clonogenic survival and proliferation capacity of glioma cells, and prolonged the survival of tumor bearing mice. Using the reactive oxygen species scavenger n-acetyl-cysteine these effects were in part reversible, suggesting that dihydroartemisinin partly acts through the generation of reactive oxygen species.

Background: Decompressive hemicraniectomy (DHC) is life-saving in patients with malignant middle cerebral artery infarction (MMI), but outcome, perspectives and complications after DHC in daily practice are largely unknown. Methods: From 2008 until 2014, we extracted patient's characteristics as well as complications from our database for patients with MMI who underwent DHC. Additionally, we analysed medical records from the different rehabilitation steps. Results: We identified 48 consecutive patients (mean 57 years, 21 male, 41.7% >60 years) with MMI who underwent DHC. The decision for DHC was made on an individual basis, including patients without impaired consciousness or stroke onset >48 h. In-hospital patients achieved only marginal clinical improvement. Seventy-five percent attended an early-rehabilitation, 44% achieved post-stroke rehabilitation and 6% carried on late-stage rehabilitation. In all, 45.5% returned home after rehabilitation. In-hospital mortality was 14.6%, overall mortality was 16.7%. Surviving patients (78.9%) had a modified Rankin Scale of 4-5. Frequent neurologic complications were symptomatic epilepsy and delirium. Following DHC/bone-flap-reimplantation, wound-healing disorders, epidural hematoma and wound infections were major surgery-related complications. Pulmonary infections were frequent in the acute-phase and urinary tract infections were predominant in the late-phase. Conclusions: DHC is a life-saving technique in patients with MMI, but complications are frequent, were underestimated in randomized clinical trials and may worsen the functional outcome.

Glioblastoma (GB) is associated with poor patient survival owing to uncontrolled tumor proliferation and resistance to apoptosis. Human ether-a-go-go-related gene K(+) channels (hERG; Kv11.1, KCNH2) are expressed in multiple cancer cells including GB and control cell proliferation and death. We hypothesized that pharmacological targeting of hERG protein would inhibit tumor growth by inducing apoptosis of GB cells. The small molecule hERG ligand doxazosin induced concentration-dependent apoptosis of human LNT-229 (EC50 = 35 µM) and U87MG (EC50 = 29 µM) GB cells, accompanied by cell cycle arrest in the G0/G1 phase. Apoptosis was associated with 64% reduction of hERG protein. HERG suppression via siRNA-mediated knock down mimicked pro-apoptotic effects of doxazosin. Antagonism of doxazosin binding by the non-apoptotic hERG ligand terazosin resulted in rescue of protein expression and in increased survival of GB cells. At the molecular level doxazosin-dependent apoptosis was characterized by activation of pro-apoptotic factors (phospho-erythropoietin-producing human hepatocellular carcinoma receptor tyrosine kinase A2, phospho-p38 mitogen-activated protein kinase, growth arrest and DNA damage inducible gene 153, cleaved caspases 9, 7, and 3), and by inactivation of anti-apoptotic poly-ADP-ribose-polymerase, respectively. In summary, this work identifies doxazosin as small molecule compound that promotes apoptosis and exerts anti-proliferative effects in human GB cells. Suppression of hERG protein is a crucial molecular event in GB cell apoptosis. Doxazosin and future derivatives are proposed as novel options for more effective GB treatment.