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SMAC Mimetic/IAP Inhibitor Birinapant Enhances Radiosensitivity of Glioblastoma Multiforme
David Cerna1, Bora Lim2, Yusuf Adelabu3
1Molecular Radiation Therapeutics Branch Support, SAIC-Frederick, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702.
Radiation Research
|April 7, 2021
Summary
Birinapant, a novel apoptosis inhibitor, enhances glioblastoma cell radiosensitivity. Combination treatment with birinapant and radiation significantly delays tumor growth and improves survival in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy
Background:
- Birinapant is a novel SMAC peptidomimetic molecule targeting inhibitor of apoptosis proteins (IAPs).
- IAP inhibition is known to sensitize cancer cells to radiation therapy.
- Glioblastoma remains a challenging cancer with limited treatment options.
Purpose of the Study:
- To investigate the radiosensitizing potential of birinapant in glioblastoma cells.
- To evaluate the efficacy of birinapant in combination with radiation therapy in vitro and in vivo.
Main Methods:
- Utilized U-251 and U-87 glioblastoma cell lines for in vitro radiosensitization assays (7-AAD, clonogenic assays).
- Employed subcutaneous and intracranial xenograft models in nude mice for in vivo evaluation.
- Measured tumor necrosis factor-alpha (TNF-α) levels using electrochemiluminescence.
Main Results:
- Birinapant demonstrated radiosensitization of glioblastoma cells, more pronounced in U-251 than U-87 cell lines.
- Combination therapy significantly delayed tumor growth in both subcutaneous and orthotopic xenograft models compared to radiation alone.
- A survival benefit was observed in the orthotopic model with combined birinapant and radiation treatment.
- Radiation-induced TNF-α levels correlated with treatment efficacy.
Conclusions:
- Birinapant effectively enhances glioblastoma radiosensitivity in vitro and in vivo.
- The combination of birinapant and radiation therapy shows promise for glioblastoma treatment.
- Radiation-induced TNF-α plays a role in the observed radiosensitization effect.
