Prevalent Brain Tumor Research Articles

Activation of multiple molecular mechanisms for apoptosis in human malignant glioblastoma T98G and U87MG cells treated with sulforaphane

Glioblastoma is the most malignant and prevalent brain tumor that still remains incurable. Recent studies reported anti-cancer effect of the broccoli-derived compound sulforaphane. We explored the mechanisms of sulforaphane-mediated apoptosis in human glioblastoma T98G and U87MG cells. Wright staining and ApopTag assay confirmed apoptosis in glioblastoma cells treated with sulforaphane. Increase in intracellular free Ca 2+ was detected by fura-2 assay, suggesting activation of Ca 2+-dependent pathways for apoptosis. Western blotting was used to detect changes in expression of Bax and Bcl-2 proteins resulting in increased Bax:Bcl-2 ratio that indicated a commitment of glioblastoma cells to apoptosis. Upregulation of calpain, a Ca 2+-dependent cysteine protease, activated caspase-12 that in turn caused activation of caspase-9. With the increased Bax:Bcl-2 ratio, cytochrome c was released from mitochondria to cytosol for sequential activation of caspase-9 and caspase-3. Increased calpain and caspase-3 activities generated 145 kD spectrin breakdown product and 120 kD spectrin breakdown product, respectively. Activation of caspase-3 also cleaved the inhibitor-of-caspase-activated-DNase. Accumulation of apoptosis-inducing-factor in cytosol suggested caspase-independent pathway of apoptosis as well. Two of the inhibitor-of-apoptosis proteins were downregulated because of an increase in ‘second mitochondrial activator of caspases/Direct inhibitor-of-apoptosis protein binding protein with low pI.’ Decrease in nuclear factor kappa B and increase in inhibitor of nuclear factor kappa B alpha expression favored the process of apoptosis. Collectively, our results indicated activation of multiple molecular mechanisms for apoptosis in glioblastoma cells following treatment with sulforaphane.

Intraoperative Consultation in the Diagnosis of Pediatric Brain Tumors

The prevalence of brain tumors in the pediatric population differs from that in the adult population. Similarly, the frequency and location of the different histologic types of brain tumors vary significantly between the pediatric and adult populations. To familiarize the pathologist with the pediatric brain tumors encountered during intraoperative consultation and with the appropriate differential diagnoses in this setting. The medical literature and the author's experience and expertise. Compared with adult brain tumors, pediatric brain tumors present different challenges and distinct differential diagnoses that the pathologist should be aware of during intraoperative consultation.

Dexamethasone protected human glioblastoma U87MG cells from temozolomide induced apoptosis by maintaining Bax:Bcl-2 ratio and preventing proteolytic activities

BackgroundGlioblastoma is the deadliest and most prevalent brain tumor. Dexamethasone (DXM) is a commonly used steroid for treating glioblastoma patients for alleviation of vasogenic edema and pain prior to treatment with chemotherapeutic drugs. Temozolomide (TMZ), an alkylating agent, has recently been introduced in clinical trials for treating glioblastoma. Here, we evaluated the modulatory effect of DXM on TMZ induced apoptosis in human glioblastoma U87MG cells.ResultsFreshly grown cells were treated with different doses of DXM or TMZ for 6 h followed by incubation in a drug-free medium for 48 h. Wright staining and ApopTag assay showed no apoptosis in cells treated with 40 μM DXM but considerable amounts of apoptosis in cells treated with 100 μM TMZ. Apoptosis in TMZ treated cells was associated with an increase in intracellular free [Ca2+], as determined by fura-2 assay. Western blot analyses showed alternations in the levels of Bax (pro-apoptotic) and Bcl-2 (anti-apoptotic) proteins resulting in increased Bax:Bcl-2 ratio in TMZ treated cells. Western blot analyses also detected overexpression of calpain and caspase-3, which cleaved 270 kD α-spectrin at specific sites for generation of 145 and 120 kD spectrin break down products (SBDPs), respectively. However, 1-h pretreatment of cells with 40 μM DXM dramatically decreased TMZ induced apoptosis, decreasing Bax:Bcl-2 ratio and SBDPs.ConclusionOur results revealed an antagonistic effect of DXM on TMZ induced apoptosis in human glioblastoma U87MG cells, implying that treatment of glioblastoma patients with DXM prior to chemotherapy with TMZ might result in an undesirable clinical outcome.

Local Treatment of Brain Tumors with Targeted Chimera Cytotoxic Proteins

High-grade astrocytomas (HGA) are the most prevalent brain tumors that represent a unique pharmaceutical challenge. Their cerebral localization and characteristic features of tumor progression primarily dictate this challenge. Targeted chimera conjugate/fusion cytotoxic proteins have become the newest class of investigative drug candidates for the treatment of HGA due to their inherent properties that are compatible with drug deliveries to brain tumors. A conjugate of a human transferrin with bacterial toxin, Diphtheria toxin, has shown clinical efficacy in Phase I and II trials when administered intratumorally through convection-enhanced delivery. This immunotoxin belongs to the first group of immunotoxins that started to live up to early expectations. Other anti-brain tumor cytotoxins have entered or will enter the clinic shortly. The clinical applicability of targeted bacterial toxin-containing cytotoxins in the treatment of brain tumors warrants further development and careful clinical evaluation.