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 proautophagic 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.
Keywords: Apoptosis, autophagy, death receptor, caspase, Bcl-2, inhibitor of apoptosis, mTOR, Akt, lysosomal protease, Beclin1, Glioblastoma, caspase-dependent apoptosis, tumor cells, autophagic cell death, CANCER, Apaf-1, caspase recruitment domain, programmed cell death, autophagosomes, malignant gliomas, apoptotic peptidase activating factor 1, cytochrome c, tuberous sclerosis 1, PI3 kinase, tumor necrosis factor, deathinducing signaling complex, antineoplastic agents, temozolomide, proteasome inhibitors, histone deacetylase inhibitors, mammalian target of rapamycin, IAP inhibitors, Mithramycin A, anti-XIAP therapy, adenine nucleotide translocator-1, mitochondrial permeability pore, Bcl-2 homology domains, Bcl-2-homolgy domain-3, ABT-263, ABT-737, Bcl-2 antisense oligonucleotide, chronic lymphocytic leukemia, CYT997, Atg6/Beclin1, pyruvate dehydrogenase kinase, growth hormone-releasing hormone, phosphatidylinositol 3-kinase, Rapamycin, Temsirolimus, Perifosine, XL765, microtubule-associated proteins, tetrahydrocannabinol, p53, Nutlins, CNS neoplasms
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