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.
Highlights
Cancer metabolism is an attractive target in tumors, especially those that are largely resistant against radioand chemotherapy
physical exercise (PE) slows down tumor growth but does not induce a differential stress response To test the effects of PE in the context of GB chemotherapy with TMZ, mice were habituated to daily moderate endurance training on a treadmill
It has been observed that PE has positive effects in the primary and secondary prevention of breast and colon cancer, and that exercise is a strong independent predictor of survival in malignant recurrent glioma [5]
Summary
Cancer metabolism is an attractive target in tumors, especially those that are largely resistant against radioand chemotherapy. As tumor cells rely more on anaerobic glycolysis compared with non-tumor cells, which is called the Warburg effect, glycolysis inhibitors were tested in cancer therapy [1]. This strategy has been pursued for many years and many different compounds are available there is only a very limited amount of clinical trials testing glycolysis inhibitors and, to our knowledge, no inhibitor has been approved for cancer therapy yet [2]. Life style factors which could influence cancer metabolism have for many years been the focus of epidemiologic studies [3,4,5,6], and the influence of eating habits and physical exercise (PE) on cardiovascular morbidity and mortality is well known. PE has been shown to have beneficial effects in primary and secondary prevention of breast and colon cancer [7,8,9,10,11] and may reduce cancer-related fatigue [12, 13]
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