Currently, application of TMZ is an integral part of the treatment of GBM. Therefore, we anticipate that future rationally designed combination treatment schemes of TMZ with new drugs, such as TRAIL, may show significant therapeutic activity in GBM. Preclinical studies have also evaluated the combination of sTRAIL with a variety of novel therapeutic BYL719 in vivo approaches for potential synergistic pro-apoptotic activity (for overview see Figure 1). The results of all these studies clearly demonstrate the added benefit of combination therapy on TRAIL-mediated cytotoxicity. Of particular interest for GBM is the combination treatment of cells
with TRAIL and proteasome inhibitor bortezomib. Bortezomib inhibits the ubiquitin-proteasome pathway, which controls the timely removal and degradation of the majority of cellular proteins . An important feature of bortezomib is the differential response of normal and cancer cells to treatment . Both normal and cancer cells are growth-arrested in the G2/M phase of the cell Alectinib manufacturer cycle. However, whereas cancer cells die by apoptosis, normal cells resume division after treatment. Bortezomib has been shown to potently augment the apoptotic activity of other therapeutics, including TRAIL . Notably, primary TRAIL-resistant GBM cells were highly sensitive to combination treatment with bortezomib and TRAIL . Another interesting candidate is the
antibiotic rapamycin, which inhibits the pro-survival Akt-mTOR pathway by inhibiting mTOR. Akt pro-survival signalling is often up-regulated in glioblastoma and therapeutic inhibition appears warranted. Importantly, rapamycin sensitizes Selleck Decitabine cells to TRAIL-mediated apoptotic signalling. The Akt-mTOR pathway is causally linked to phosphatase and tensin homolog status of glioblastoma cells, which may be used to enable the identification of a subset of patients that would benefit from rapamycin–TRAIL combination therapy . Also X-linked inhibitory apoptotic protein antagonists are used in combination with TRAIL. Clinical
studies with antisense oligonucleotide targeting X-linked inhibitory apoptotic proteins are ongoing . As described above, the intrinsic mitochondrial pathway of apoptosis is regulated by the balance between pro- and anti-apoptotic members of the Bcl-2 family . In GBM, anti-apoptotic proteins, such as Bcl-2, are frequently overexpressed, leading to cell survival. Selective inhibition of these anti-apoptotic proteins has been successfully pursued using the small molecule ABT-737, a mimetic for Bcl-2 and Bcl-xL . ABT-737 has shown prominent activity towards various different types of tumour. Recently, ABT-737 was also shown to markedly prolong survival in an intracranial xenograft GBM model . Moreover, ABT-737 synergistically enhanced the activity of sTRAIL as well as standard chemotherapeutic drugs in GBM cells.