Therapeutic exploitation of apoptosis and autophagy for glioblastoma.
Induction of caspase-dependent apoptosis (type I cell death) is a major mechanism by which most chemotherapeutic drugs and radiation kill tumor cells. However, conventional cancer therapies fail to mediate their effects in a target-specific fashion. The extremely unfavorable prognosis for patients suffering from glioblastomas (GBMs) is strongly correlated to the intrinsic apoptosis resistance of GBM cells which especially occurs in diffusely migrating tumor cells. The ultimate goal for molecular, apoptosis-based therapies is to target specific components of the two major apoptotic pathways, i.e. the extrinsic and the intrinsic pathway to trigger tumor-selective apoptosis, while at the same time limiting toxicity in normal tissues. Induction of autophagic cell death (type II cell death) by pro-autophagic drugs is an alternative and emerging concept to trigger glioma cell death and to exploit caspase-independent programmed cell death pathways for the development of novel glioma therapies. This review provides an up to date and comprehensive report on the relevant pre-clinical and clinical drugs interfering with the major apoptosis and autophagy pathways, their therapeutic potential in glioma and adresses potential future perspectives in this exciting field of research.
Kögel
Donat
D
Center for Neurology and Neurosurgery, Goethe University Hospital, Goethe University, Frankfurt, Germany. koegel@em.uni-frankfurt.de
Fulda
Simone
S
Mittelbronn
Michel
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002986:Clinical Trials as Topic; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53