TY  - JOUR
A1  - Zakaria, Zaitun
A1  - Tivnan, Amanda
A1  - Flanagan, Lorna
A1  - Murray, David W.
A1  - Salvucci, Manuela
A1  - Stringer, Brett W.
A1  - Day, Bryan W.
A1  - Boyd, Andrew W.
A1  - Kögel, Donat
A1  - Rehm, Markus
A1  - O'Brien, Donncha F.
A1  - Byrne, Annette T.
A1  - Prehn, Jochen H. M.
T1  - Patient-derived glioblastoma cells show significant heterogeneity in treatment responses to the inhibitor-of-apoptosis-protein antagonist birinapant
T2  - British journal of cancer
N2  - Background: Resistance to temozolomide (TMZ) greatly limits chemotherapeutic effectiveness in glioblastoma (GBM). Here we analysed the ability of the Inhibitor-of-apoptosis-protein (IAP) antagonist birinapant to enhance treatment responses to TMZ in both commercially available and patient-derived GBM cells.
Methods: Responses to TMZ and birinapant were analysed in a panel of commercial and patient-derived GBM cell lines using colorimetric viability assays, flow cytometry, morphological analysis and protein expression profiling of pro- and antiapoptotic proteins. Responses in vivo were analysed in an orthotopic xenograft GBM model.
Results: Single-agent treatment experiments categorised GBM cells into TMZ-sensitive cells, birinapant-sensitive cells, and cells that were insensitive to either treatment. Combination treatment allowed sensitisation to therapy in only a subset of resistant GBM cells. Cell death analysis identified three principal response patterns: Type A cells that readily activated caspase-8 and cell death in response to TMZ while addition of birinapant further sensitised the cells to TMZ-induced cell death; Type B cells that readily activated caspase-8 and cell death in response to birinapant but did not show further sensitisation with TMZ; and Type C cells that showed no significant cell death or moderately enhanced cell death in the combined treatment paradigm. Furthermore, in vivo, a Type C patient-derived cell line that was TMZ-insensitive in vitro and showed a strong sensitivity to TMZ and TMZ plus birinapant treatments.
Conclusions: Our results demonstrate remarkable differences in responses of patient-derived GBM cells to birinapant single and combination treatments, and suggest that therapeutic responses in vivo may be greatly affected by the tumour microenvironment.
KW  - Apoptosis
KW  - Chemotherapy
KW  - CNS cancer
Y1  - 2016
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/50810
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-508106
SN  - 1532-1827
SN  - 0007-0920
N1  - From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/
VL  - 114
IS  - 2
SP  - 188
EP  - 198
PB  - Nature Publ. Group
CY  - Edinburgh
ER  -