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Abstract
Glioblastoma multiforme (GBM) is a highly heterogeneous and aggressive brain tumor with a dismal prognosis. Development of resistance towards cytostatic drugs like the GBM standard drug temozolomide is a severe problem in GBM treatment. One potential source of GBM relapse could be so called cancer stem like cells (CSCs). These represent an undifferentiated subpopulation of cells with high potential for tumor initiation. Furthermore, it has been shown that differentiated GBM cells can regain CSC properties when exposed to continuous temozolomide treatment in vitro. In this study, treatment of several primary GBM cell lines with clinically relevant doses of temozolomide increased their tumorigenicity as determined by colony formation assays in soft agar. Increased tumorigenicity is a known property of CSCs. Hence, therapy options that specifically target CSCs are under investigation. CSCs appear to be particularly dependent on mitochondria biogenesis which may represent a useful target for CSC elimination. Toxicity towards mitochondria is a known side effect of several antibiotics. Thus, addition of antibiotics like doxycycline may represent a useful tool to inhibit CSCs in GBM. Here, we show that combining temozolomide treatment of primary GBM cells with doxycycline could counteract the increase of tumorigenicity induced by temozolomide treatment.
Highlights
Glioblastoma multiforme (GBM) is a highly malignant brain tumor associated with a median survival of only 12 to 15 months despite aggressive multimodal standard treatment, consisting of resection followed by radio- and chemotherapy [1,2]
Drug resistance is a major challenge of GBM treatment
GBM-cancer stem-like cells (CSCs) can differentiate into several neural cell lineages like astrocytes, oligodendrocytes or glia cells, enhancing the tumor mass [22]
Summary
Glioblastoma multiforme (GBM) is a highly malignant brain tumor associated with a median survival of only 12 to 15 months despite aggressive multimodal standard treatment, consisting of resection followed by radio- and chemotherapy [1,2]. The development of resistance towards cytostatic drugs like the first line drug temozolomide is a problem for GBM treatment, and relapses of the disease are common [3]. One potential source of resistance and relapses are the so-called cancer stem-like cells (CSCs) within those tumors [4,5]. Temozolomide-induced tumorigenicity can be diminished by targeting of mitochondria in glioblastoma cell lines tumor (re-)initiation [6,7,8]. CSCs show expression of proteins associated with a physiological stem or progenitor cell state, for example CD133, CD15 and nestin [9]. The direct targeting of CSCs might be a promising strategy for GBM treatment
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