Slowing down glioblastoma progression in mice by running or the anti-malarial drug dihydroartemisinin? Induction of oxidative stress in murine glioblastoma therapy.

// Dieter Lemke 1, 2, 3 , Hans-Werner Pledl 1, 2, 3 , Markus Zorn 4 , Manfred Jugold 5 , Ed Green 1, 6 , Jonas Blaes 1, 2 , Sarah Low 1, 2, 3 , Anne Hertenstein 1, 2, 3 , Martina Ott 1, 6 , Felix Sahm 1, 7, 8 , Ann-Catherine Steffen 1, 2 , Markus Weiler 1, 2, 3 , Frank Winkler 1, 2, 3 , Michael Platten 1, 3, 6 , Zhen Dong 9, * , Wolfgang Wick 1, 2, 3, * 1 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany 2 Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany 3 Neurology Clinic and National Center for Tumor Diseases, University of Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany 4 Central Laboratory of Heidelberg University Hospital, German Cancer Research Center (DKFZ), Heidelberg, Germany 5 Core Facility Small Animal Imaging Center, German Cancer Research Center (DKFZ), Heidelberg, Germany 6 Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany 7 Department of Neuropathology, Institute of Pathology, University of Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany 8 Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany 9 Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China * These authors have shared senior authorship Correspondence to: Zhen Dong, email: dongz@tjh.tjmu.edu.cn Wolfgang Wick, email: wolfgang.wick@med.uni-heidelberg.de Keywords: dihydroartemisinin, glioblastoma, physical exercises (PE), therapy, physical exercise Received: May 11, 2016      Accepted: June 14, 2016      Published: July 20, 2016 ABSTRACT 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.