Pro-inflammatory genes as biomarkers and therapeutic targets in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is a major health problem worldwide, and patients have a particularly poor 5-year survival rate. Thus, identification of the molecular targets in OSCC and subsequent innovative therapies are greatly needed. Prolonged exposure to alcohol, tobacco, and pathogenic agents are known risk factors and have suggested that chronic inflammation may represent a potential common denominator in the development of OSCC. Microarray analysis of gene expression in OSCC cell lines with high basal NF-κB activity and OSCC patient samples identified dysregulation of many genes involved in inflammation, wound healing, angiogenesis, and growth regulation. In particular IL-8, CCL5, STAT1, and VEGF gene expression was up-regulated in OSCC. Moreover, IL-8 protein levels were significantly higher in OSCC cell lines as compared with normal human oral keratinocytes. Targeting IL-8 expression by siRNA significantly reduced the survival of OSCC cells, indicating that it plays an important role in OSCC development and/or progression. Inhibiting the inflammatory pathway by aspirin and the proteasome/NF-κB pathway by bortezomib resulted in marked reduction in cell viability in OSCC lines. Taken together our studies indicate a strong link between inflammation and OSCC development and reveal IL-8 as a potential mediator. Treatment based on prevention of general inflammation and/or the NF-κB pathway shows promise in OSCCs.

A survey of glioblastoma genomic amplifications and deletions.

Glioblastoma Multiforme (GBM) is a malignant brain cancer that develops after accumulating genomic DNA damage that often includes gene amplifications and/or deletions. These copy number changes can be a critical step in brain tumor development. To evaluate glioblastoma genomic copy number changes, we determined the genome-wide copy number alterations in 31 GBMs. Illumina Bead Arrays were used to assay 22 GBMs and Digital Karyotyping was used on 8 GBM cell lines and one primary sample. The common amplifications we observed for all 31 samples was GLI/CDK4 (22.6%), MDM2 (12.9%) and PIK3C2B/MDM4 (12.9%). In the 22 GBM tumors, EGFR was amplified in 22.7% of surgical biopsies. The most common homozygously deleted region contained CDKN2A/CDKN2B (p15 and p16) occurring in 29% of cases. This data was compiled and compared to published array CGH studies of 456 cases of GBMs. Pooling our Illumina data with published studies yielded these average amplification rates: EGFR-35.7%, GLI/CDK4-13.4%, MDM2-9.2%, PIK3C2B/MDM4-7.7%, and PDGFRA-7.7%. The CDKN2A/CDKN2B locus was deleted in 46.4% of the combined cases. This study provides a larger assessment of amplifications and deletions in glioblastoma patient populations and shows that several different copy number technologies can produce similar results. The main pathways known to be involved in GBM tumor formation such as p53 control, growth signaling, and cell cycle control are all represented by amplifications or deletions of critical pathway genes. This information is potentially important for formulating targeted therapy in glioblastoma and for planning genomic studies.

Biochemical changes induced in liver and serum of diplodiatoxin (Stenocarpella maydis) treated male and female rats.

Present study was conducted to investigate the acute and sub-acute toxic effect of diplodiatoxin with special reference to biochemical membrane bound enzymes like aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT) and RBC acetylcholinesterase (AChE) in male and female rats. For acute study, rats were treated with a single oral dose of 5.7 mg/kg of diplodiatoxin, whereas for sub-acute study, the rats received 0.27 mg/kg/day for 21 days. Acute and sub-acute diplodiatoxin treatment caused loss in body weight and feed intake along with symptoms including irritation, dullness, tremors and convulsions. Diplodiatoxin caused a significant increase in serum ASAT and ALAT and a decrease in activity in the liver in both acute and sub-acute studies. This compound also significantly inhibited RBC AChE. Sexual dimorphism was observed when male rats were compared with female rats (p < 0.05). The enzyme alterations observed in the affected enzymes recovered to the normal levels by day 7 post treatment (withdrawal study) in both acute and sub-acute treated rats. A negative correlation was observed with regard to these enzymes when serum was compared with liver. These enzyme profiles show increases in serum with parallel decrease in liver, indicating necrosis of liver. These results suggest that diplodiatoxin has potential to affect hepatic end-points.

Effect of diplodiatoxin (Stenocarpella maydis) on some enzymatic profiles in male and female rats.

Acute and subacute effects of diplodiatoxin were monitored with special reference to biochemical target enzymes like acid phosphatase (AcP), alkaline phosphatase (AkP), and acetylcholinesterase (AChE) in male and female rats. For acute toxicity study the rats were treated with single oral dose of 5.7 mg/kg of diplodiatoxin, whereas for subacute toxicity study the rats were orally treated with 0.27 mg/kg/day for 21 days. Diplodiatoxin caused loss in body weight and feed intake with other clinical symptoms. Due to the acute and subacute treatment of diplodiatoxin significant decreases were observed in serum AcP and AkP and also in liver AkP, whereas liver AcP increased in both male and female treated rats. Further, significant inhibition of brain AChE was observed in acute and subacute treated animals, indicating its effect on nerve synapsis. Sexual dimorphism was recorded when the activity of male rats was compared with female rats. The values were near those of controls on Day 7 (posttreatment), indicating recovery in the altered enzymes once the treatment was ceased. These results suggest that diplodiatoxin is toxic and has potential to affect the normal functioning of individuals and can cause changes in vital tissues such as liver.