DNA microarray profiling of genes differentially regulated by the histone deacetylase inhibitors vorinostat and LBH589 in colon cancer cell lines

<p>Abstract</p> <p>Background</p> <p>Despite the significant progress made in colon cancer chemotherapy, advanced disease remains largely incurable and novel efficacious chemotherapies are urgently needed. Histone deacetylase inhibitors (HDACi) represent a novel class of agents which have demonstrated promising preclinical activity and are undergoing clinical evaluation in colon cancer. The goal of this study was to identify genes in colon cancer cells that are differentially regulated by two clinically advanced hydroxamic acid HDACi, vorinostat and LBH589 to provide rationale for novel drug combination partners and identify a core set of HDACi-regulated genes.</p> <p>Methods</p> <p>HCT116 and HT29 colon cancer cells were treated with LBH589 or vorinostat and growth inhibition, acetylation status and apoptosis were analyzed in response to treatment using MTS, Western blotting and flow cytometric analyses. In addition, gene expression was analyzed using the Illumina Human-6 V2 BeadChip array and Ingenuity^®Pathway Analysis.</p> <p>Results</p> <p>Treatment with either vorinostat or LBH589 rapidly induced histone acetylation, cell cycle arrest and inhibited the growth of both HCT116 and HT29 cells. Bioinformatic analysis of the microarray profiling revealed significant similarity in the genes altered in expression following treatment with the two HDACi tested within each cell line. However, analysis of genes that were altered in expression in the HCT116 and HT29 cells revealed cell-line-specific responses to HDACi treatment. In addition a core cassette of 11 genes modulated by both vorinostat and LBH589 were identified in both colon cancer cell lines analyzed.</p> <p>Conclusion</p> <p>This study identified HDACi-induced alterations in critical genes involved in nucleotide metabolism, angiogenesis, mitosis and cell survival which may represent potential intervention points for novel therapeutic combinations in colon cancer. This information will assist in the identification of novel pathways and targets that are modulated by HDACi, providing much-needed information on HDACi mechanism of action and providing rationale for novel drug combination partners. We identified a core signature of 11 genes which were modulated by both vorinostat and LBH589 in a similar manner in both cell lines. These core genes will assist in the development and validation of a common gene set which may represent a molecular signature of HDAC inhibition in colon cancer.</p

Mechanisms of Cisplatin Nephrotoxicity

Cisplatin is a widely used and highly effective cancer chemotherapeutic agent. One of the limiting side effects of cisplatin use is nephrotoxicity. Research over the past 10 years has uncovered many of the cellular mechanisms which underlie cisplatin-induced renal cell death. It has also become apparent that inflammation provoked by injury to renal epithelial cells serves to amplify kidney injury and dysfunction in vivo. This review summarizes recent advances in our understanding of cisplatin nephrotoxicity and discusses how these advances might lead to more effective prevention

Behavior of NDMA precursors at 21 full-scale water treatment facilities

A source-to-tap evaluation of the origin and fate of chloramination N-nitrosodimethylamine (NDMA) precursors at 21 full-scale drinking water plants was conducted. Upstream wastewater discharges accounted for (on a median basis) similar to 16 ng L-1 NDMA formation potential (FP). A correlation between concentrations of the artificial sweetener sucralose (wastewater tracer) and NDMA FP was found within certain watersheds, with increased river flow decreasing sucralose and NDMA FP concentrations by diluting the wastewater discharges. The polymers polydiallyldimethylammonium chloride (polyDADMAC) and polyamine contributed (median) 6 and 14 ng L-1 of NDMA FP to coagulated water (which was pre-chloraminated in two cases), respectively. Biofiltration increased NDMA FP by (median) 6 ng L-1; biofiltration tended to increase precursor loading rather than reduce it. Although wastewater and polymers are known sources of precursors, biofilters as a source of precursors was an important finding. Ozonation of raw or settled water was effective at destroying NDMA precursors (median 34%). As free chlorine exposure increased (from 1 h), NDMA formation in the chloraminated distribution system decreased (from median removal of 21% to 90% of the NDMA FP sampled prior to chlorination). For either oxidant, precursor abatement was typically higher at pH similar to 8-9 than at 7. Riverbank filtration, and powdered and granular activated carbon removed (median) 64, 47, and 64% of watershed-derived NDMA precursors, respectively. Each was able to remove NDMA FP better than that of the bulk total organic carbon. Granular activated carbon did not appear to be effective at removing polyDADMAC-derived precursors added during coagulation. The contribution of different watershed or in-plant sources to NDMA precursors varies by plant and over time and, depending upon precursor sources, different in-plant treatment strategies can effectively control NDMA formation