Small-molecule XIAP inhibitors enhance gamma-irradiation-induced apoptosis in glioblastoma.
Because evasion of apoptosis can cause radioresistance of glioblastoma, there is a need to design rational strategies that counter apoptosis resistance. In the present study, we investigated the potential of targeting the antiapoptotic protein XIAP for the radiosensitization of glioblastoma. Here, we report that small-molecule XIAP inhibitors significantly enhance gamma-irradiation-induced loss of viability and apoptosis and cooperate with gamma-irradiation to suppress clonogenic survival of glioblastoma cells. Analysis of molecular mechanisms reveals that XIAP inhibitors act in concert with gamma-irradiation to cause mitochondrial outer membrane permeabilization, caspase activation, and caspase-dependent apoptosis. Importantly, XIAP inhibitors also sensitize primary cultured glioblastoma cells derived from surgical specimens as well as glioblastoma-initiating stemlike cancer stem cells for gamma-irradiation. In contrast, they do not increase the toxicity of gamma-irradiation on some nonmalignant cells of the central nervous system, including rat neurons or glial cells, pointing to some tumor selectivity. In conclusion, by demonstrating for the first time that small-molecule XIAP inhibitors increase the radiosensitivity of glioblastoma cells while sparing normal cells of the central nervous system, our findings build the rationale for further (pre)clinical development of XIAP inhibitors in combination with gamma-irradiation in glioblastoma.
Vellanki
Sri Hari Krishna
SH
University Children's Hospital, Ulm University, D-89075 Ulm, Germany.
Grabrucker
Andreas
A
Liebau
Stefan
S
Proepper
Christian
C
Eramo
Adriana
A
Braun
Veit
V
Boeckers
Tobias
T
Debatin
Klaus-Michael
KM
Fulda
Simone
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D015153:Blotting, Western; D020169:Caspases / Q000187:drug effects; D003131:Combined Modality Therapy; D053938:DNA Fragmentation / Q000187:drug effects / Q000528:radiation effects; D005434:Flow Cytometry; D005720:Gamma Rays / Q000627:therapeutic use*; D005909:Glioblastoma / Q000628:therapy*; D006801:Humans; D007150:Immunohistochemistry; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000528:radiation effects; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D051381:Rats; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors* / Q000187:drug effects
D011838:Radiation-Sensitizing Agents; D051636:X-Linked Inhibitor of Apoptosis Protein; D020169:Caspases