The hypoxia-inducible factor 1alpha (HIF-1alpha) plays a major role in cancer progression. The role of this transcription factor in prostate cancer development and its transition to a metastatic and androgen refractory state remains to be elucidated. Previous reports have identified the existence of single nucleotide polymorphisms (SNPs) in the oxygen-dependent degradation domain of the HIF-1alpha gene in renal cell carcinoma, head and neck squamous cell carcinoma, and androgen-independent prostate cancer (AIPC). Studies in prostate cancer, however, are variable and limited in the number of cases assessed. Herein we further investigate these SNPs, specifically C1772T (which results in an amino acid change from proline 582 to serine) and G1790A (alanine 588 to threonine). The frequency of these polymorphisms was evaluated in a population of individuals with metastatic AIPC and compared to a set of healthy control subjects. The distribution of HIF-1alpha genotypes for C1772T in 196 AIPC patients was 161 C/C (82.1%), 29 C/T (14.8%), and 6 T/T (3.1%). The genotype distribution in 196 controls was 179 C/C (91.3%), 14 C/T (7.1%), and 3 T/T (1.5%). Our results demonstrate a significant difference in genotype distribution between AIPC patients and control subjects only for the C1772T polymorphism (p = 0.024). The association of the incidence of the polymorphism with overall survival was determined to be not statistically significant (p = 0.93) by the Mantel-Haenszel (log-rank) test. These results suggest that the C1772T polymorphism in HIF-1alpha may confer susceptibility to AIPC and contribute to the progression or metastasis of this disease.
Toxic industrial chemicals induce liver injury, which is difficult to diagnose without invasive procedures. Identifying indicators of end organ injury can complement exposure-based assays and improve predictive power. A multiplexed approach was used to experimentally evaluate a panel of 67 genes predicted to be associated with the fibrosis pathology by computationally mining DrugMatrix, a publicly available repository of gene microarray data. Five-day oral gavage studies in male Sprague Dawley rats dosed with varying concentrations of 3 fibrogenic compounds (allyl alcohol, carbon tetrachloride, and 4,4'-methylenedianiline) and 2 nonfibrogenic compounds (bromobenzene and dexamethasone) were conducted. Fibrosis was definitively diagnosed by histopathology. The 67-plex gene panel accurately diagnosed fibrosis in both microarray and multiplexed-gene expression assays. Necrosis and inflammatory infiltration were comorbid with fibrosis. ANOVA with contrasts identified that 51 of the 67 predicted genes were significantly associated with the fibrosis phenotype, with 24 of these specific to fibrosis alone. The protein product of the gene most strongly correlated with the fibrosis phenotype PCOLCE (Procollagen C-Endopeptidase Enhancer) was dose-dependently elevated in plasma from animals administered fibrogenic chemicals (P < .05). Semiquantitative global mass spectrometry analysis of the plasma identified an additional 5 protein products of the gene panel which increased after fibrogenic toxicant administration: fibronectin, ceruloplasmin, vitronectin, insulin-like growth factor binding protein, and α2-macroglobulin. These results support the data mining approach for identifying gene and/or protein panels for assessing liver injury and may suggest bridging biomarkers for molecular mediators linked to histopathology.
Many heavy metals, including nickel (Ni), cadmium (Cd), and chromium (Cr) are toxic industrial chemicals with an exposure risk in both occupational and environmental settings that may cause harmful outcomes. While these substances are known to produce adverse health effects leading to disease or health problems, the detailed mechanisms remain unclear. To elucidate the processes involved in the toxicity of nickel, cadmium, and chromium at the molecular level and to perform a comparative analysis, H4-II-E-C3 rat liver-derived cell lines were treated with soluble salts of each metal using concentrations derived from viability assays, and gene expression patterns were determined with DNA microarrays. We identified both common and unique biological responses to exposure to the three metals. Nickel, cadmium, chromium all induced oxidative stress with both similar and unique genes and pathways responding to this stress. Although all three metals are known to be genotoxic, evidence for DNA damage in our study only exists in response to chromium. Nickel induced a hypoxic response as well as inducing genes involved in chromatin structure, perhaps by replacing iron in key proteins. Cadmium distinctly perturbed genes related to endoplasmic reticulum stress and invoked the unfolded protein response leading to apoptosis. With these studies, we have completed the first gene expression comparative analysis of nickel, cadmium, and chromium in H4-II-E-C3 cells.
Purpose: The herbal supplement garlic (Allium sativum) is commonly used by cancer patients.Preclinical studies have shown that allicin, a major component of garlic, may affect cytochrome P450 3A4 (CYP3A4) activity.This study examines the influence of garlic supplementation on the pharmacokinetics of docetaxel, a CYP3A4 substrate. Experimental Design: Women with metastatic breast cancer were treated with docetaxel (30 mg/m 2 ) given weekly for 3 of 4 weeks. Three days after the initial dose of docetaxel, patients received 600 mg of garlic twice daily for 12 consecutive days. Docetaxel pharmacokinetics were assessed during the first three administrations. Results: In 10 evaluable patients, the mean baseline clearance of docetaxel was 30.8 L/h/m 2 [95% confidence intervals (95% CI), 16.7-44.9]. Coadministration of garlic reduced mean clearance of docetaxel to 23.7 L/h/m 2 (95% CI, 15.5-31.8) and 20.0 L/h/m 2 (95% CI, 13.3-26.7) on days 8 and 15, respectively (P = 0.17). Additional pharmacokinetic variables of docetaxel, including peak concentration (P = 0.79), area under the curve (P = 0.36), volume of distribution (P = 0.84), and half-life (P = 0.36), were also not statistically significantly different. The mean area under the curve ratio between day 15 and day 1 was 3.74 in three individuals with the CYP3A5*1A/*1A genotype (all African American) compared with 1.02 in six individuals with the CYP3A5*3C/*3C genotype (all Caucasian). Conclusions: This study indicates that garlic does not significantly affect the disposition of docetaxel. However, it cannot be excluded that garlic decreases the clearance of docetaxel in patients carrying a CYP3A5*1A allele.
Cobalt is a transition group metal present in trace amounts in the human diet, but in larger doses it can be acutely toxic or cause adverse health effects in chronic exposures. Its use in many industrial processes and alloys worldwide presents opportunities for occupational exposures, including military personnel. While the toxic effects of cobalt have been widely studied, the exact mechanisms of toxicity remain unclear. In order to further elucidate these mechanisms and identify potential biomarkers of exposure or effect, we exposed two rat liver-derived cell lines, H4-II-E-C3 and MH1C1, to two concentrations of cobalt chloride. We examined changes in gene expression using DNA microarrays in both cell lines and examined changes in cytoplasmic protein abundance in MH1C1 cells using mass spectrometry. We chose to closely examine differentially expressed genes and proteins changing in abundance in both cell lines in order to remove cell line specific effects. We identified enriched pathways, networks, and biological functions using commercial bioinformatic tools and manual annotation. Many of the genes, proteins, and pathways modulated by exposure to cobalt appear to be due to an induction of a hypoxic-like response and oxidative stress. Genes that may be differentially expressed due to a hypoxic-like response are involved in Hif-1α signaling, glycolysis, gluconeogenesis, and other energy metabolism related processes. Gene expression changes linked to oxidative stress are also known to be involved in the NRF2-mediated response, protein degradation, and glutathione production. Using microarray and mass spectrometry analysis, we were able to identify modulated genes and proteins, further elucidate the mechanisms of toxicity of cobalt, and identify biomarkers of exposure and effect in vitro, thus providing targets for focused in vivo studies.
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