Temozolomide sensitizes stem-like cells of glioma spheres to TRAIL-induced apoptosis via upregulation of casitas B-lineage lymphoma (c-Cbl) protein.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has potent antitumor effects in glioma cell lines but has shown little clinical benefit for patients. We investigated whether the widely used chemotherapeutic agent temozolomide (TMZ) can sensitize glioma stem-like cells (GSCs) from human glioblastoma multiforme (GBM) to TRAIL-induced apoptosis. GSCs were isolated from GBM, and stem cell properties were confirmed by immunocytochemistry and in vivo tumorigenicity. Primary GSCs (PGCs) were produced by serum treatment of GBM-derived cells. Changes in expression levels of various TRAIL-related signaling factors before and after TRAIL or TRAIL + TMZ treatment were measured by Western blotting. Overexpression vectors and siRNAs were used to investigate mechanism of TRAIL sensitivity. GSCs showed greater resistance to TRAIL-induced apoptosis than PGCs and had lower basal caspase activity. Caspase knockdown in PGCs reduced TRAIL sensitivity. Expression levels of c-Fas-associated death domain-like interleukin 1-converting enzyme-like inhibitory protein long and short isoforms (c-FLIPL and c-FLIPS) were significantly higher in GSCs than PGCs, and siRNA-mediated c-FLIP knockdown in GSCs enhanced TRAIL-induced apoptosis. TMZ enhanced TRAIL-induced apoptosis in GSCs and downregulated c-FLIP expression. Add of TMZ also upregulated the expression of the E3 ubiquitin ligase casitas B-lineage lymphoma (c-Cbl). Moreover, overexpression of c-Cbl alone reduced c-FLIP expression, and c-Cbl knockdown both enhanced c-FLIP expression and reduced the potentiating effect of TMZ on TRAIL-induced apoptosis. The result indicated that TMZ may overcome TRAIL resistance in GSCs by suppressing c-FLIP expression through c-Cbl-mediated ubiquitination and degradation.

Microsurgical subtemporal approach to aneurysms on the P(2) segment of the posterior cerebral artery.

BACKGROUND: Aneurysms arising from the P(2) segment of the posterior cerebral artery (PCA) are rare, accounting for less than 1% of all intracranial aneurysms. To date, few studies concerning the management of P(2) segment aneurysms have been reported. OBJECTIVE: To review the microsurgical techniques and clinical outcomes of microsurgical treatment by different approaches in patients with aneurysms on the P(2) segment of the PCA. MATERIALS AND METHODS: Forty-two patients with P2 segment aneurysms had microsurgical treatment by subtemporal approach. All the patients had drainage of cerebrospinal fluid for decompression, and indocyanine green (ICG) angiography was used in 20 patients to assess the effect of clipping. RESULTS: Of the 42 patients, 16 were operated by combined pterional-subtemporal approach. In 40 patients aneurysms were successfully treated by clipping the P(2) aneurysmal neck while preserving the parent artery. Two patients with giant aneurysms were treated using surgical trapping. Postoperatively, 41 patients had a good recovery. One patient after aneurysm trapping had ischemic infarction in the PCA tertiary and presented with hemiparesis and homonymous hemianopia. However, this patient recovered after three weeks of treatment. CONCLUSION: Subtemporal approach is the most appropriate approach to clip the aneurysms of the P(2) segment. It allows the neurosurgeon to operate on the aneurysms while preserving the patency of the parent artery. Gaint P(2) segment aneurysms can safely be treated by rapping of the aneurysm by combined subtemporal or pterional-subtemporal approach in experienced hands. ICG angiography will be an important tool in monitoring for the presence of residual aneurysm or perforating artery occlusion during aneurysm clipping. Preoperative lumbar drainage of cerebrospinal fluid may help to avoid temporal lobe damage.