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.
Suprascapular nerve entrapment (SNE) in the suprascapular notch is a rare entity that must be considered in the differential diagnosis of radicular pain, as well as that of shoulder discomfort. Over a period of 10 years (1985-1995), the authors treated 28 cases of SNE in 27 patients by surgical decompression of the nerve. One patient underwent operation bilaterally within 5 years. Five patients presented with a history of trauma to the shoulder region. In three patients, a ganglion cyst was the origin of the nerve lesion. In 16 patients, the nerve problem was primarily related to athletic activities. Eight of these patients were professional volleyball players. In the remaining three patients, there was no relationship between the nerve lesion and trauma or athletic activities. Twenty-one patients (22 cases) complained of pain located over the suprascapular notch. Seventeen patients had paresis and atrophy of both the supraspinatus (SS) and infraspinatus (IS) muscles. In 10 patients only the IS muscle was involved. One patient exhibited a sensory deficit over the posterior portion of the shoulder. Electromyography was performed in all cases. The mean follow-up period in the 25 cases (24 patients) that could be evaluated was 20.8 months (range 3-70 months). Nineteen of 22 cases with preoperative pain could be evaluated. Sixteen of these patients were completely free of pain after surgery and three patients found their pain had improved. Motor function in the SS muscle improved in 86.7% and motor function in the IS muscle in 70.8% of cases. Atrophy of the SS muscle resolved in 80.7% and atrophy of the IS muscle in 50% of cases. Surgical treatment of SNE is indicated after failed conservative treatment and in cases of atrophy of the SS and IS muscles. The authors recommend the posterior approach, which minimizes risks and complications and produces good postoperative results.
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