Type

Journal Article

Authors

J H M Prehn
A T Byrne
D F O'Brien
M Rehm
D Kögel
A W Boyd
B W Day
B W Stringer
M Salvucci
D W Murray
and 3 others

Subjects

Biochemistry

Topics
b cells cell lines cell death caspase 8 protein expression flow cytometry apoptosis protein morphological analysis

Patient-derived glioblastoma cells show significant heterogeneity in treatment responses to the inhibitor-of-apoptosis-protein antagonist birinapant. (2015)

Abstract 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. 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. 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. 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.British Journal of Cancer advance online publication 10 December 2015; doi:10.1038/bjc.2015.420 www.bjcancer.com.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed

Full list of authors on original publication

J H M Prehn, A T Byrne, D F O'Brien, M Rehm, D Kögel, A W Boyd, B W Day, B W Stringer, M Salvucci, D W Murray and 3 others

Experts in our system

1
Jochen H M Prehn
Royal College of Surgeons in Ireland
Total Publications: 206
 
2
Annette T Byrne
Royal College of Surgeons in Ireland
Total Publications: 41
 
3
Donncha F O'Brien
Royal College of Surgeons in Ireland
Total Publications: 19
 
4
Markus Rehm
Royal College of Surgeons in Ireland
Total Publications: 55
 
5
Donat Kögel
Royal College of Surgeons in Ireland
Total Publications: 14
 
6
A W Boyd
Royal College of Surgeons in Ireland
Total Publications: 3
 
7
B W Day
Royal College of Surgeons in Ireland
Total Publications: 3
 
8
B W Stringer
Royal College of Surgeons in Ireland
Total Publications: 3
 
9
Manuela Salvucci
Royal College of Surgeons in Ireland
 
10
David W Murray
Royal College of Surgeons in Ireland
Total Publications: 15