Type

Other / n/a

Authors

Jochen Prehn
Annette Byrne
D F O'Brien
Markus Rehm
D Kögel
A W Boyd
B W Day
B W Stringer
M Salvucci
D W Murray
and 3 others

Subjects

Microbiology

Topics
medicine and health sciences patient derived glioblastoma cells cell lines physics physiology flow cytometry apoptosis protein birinapant

Patient-derived glioblastoma cells show significant heterogeneity in treatment responses to the inhibitor-of-apoptosis-protein antagonist birinapant. (2016)

Abstract 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.
Collections Ireland -> Royal College of Surgeons in Ireland -> Physiology and Medical Physics Articles
Ireland -> Royal College of Surgeons in Ireland -> Department of Physiology and Medical Physics

Full list of authors on original publication

Jochen Prehn, Annette Byrne, D F O'Brien, Markus 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