herbimycin and Pancreatic-Neoplasms

Topics: Animals; Blotting, Western; Cattle; Cell Line; Cell Line, Tumor; Cell Movement; Crk-Associated Substrate Protein; Endothelial Cells; Enzyme Inhibitors; Focal Adhesion Protein-Tyrosine Kinases; Humans; Neoplasm Invasiveness; Pancreatic Neoplasms; Phosphorylation; Pulmonary Artery; Rifabutin; Tyrosine

We attempted to determine potential therapeutic targets in pancreatic cancer by performing microarray analysis and targeted chemotherapy on three human pancreatic cancer cell lines. We used a microarray to screen 847 genes involved in cytokine signaling, signal transduction, and transcription. Tyrosine kinases represented a common target driving proliferation among the three cell types. We tested the ability of Gleevec (STI-571), Lavendustin, Herbimycin, and Genistein to inhibit the proliferation of cells in culture as assessed by the MTT assay.Eighteen genes were found to be commonly expressed by the three cell lines. Of these, six (33%) included tyrosine phosphorylation signaling as part of the pathway. The most highly expressed common transcript was the EphB3 receptor, which is a tyrosine kinase. Herbimycin and Genistein were able to inhibit the proliferation of all three cell lines in a dose dependent manner, with a mean IC(50) of 1.71 microM and 223 microM, respectively; whereas Lavendustin and Gleevec were ineffective in the inhibition of proliferation. Transcriptional profiling yielded common targets and insights into the biology of cells in culture. Herbimycin- and Genistein-based kinase inhibitors may offer potential and should be tested in other in vivo models for their ability to inhibit the growth of pancreatic cancer.

Topics: Benzamides; Benzoquinones; Cell Division; Cell Line, Tumor; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Genistein; Humans; Imatinib Mesylate; Lactams, Macrocyclic; Oligonucleotide Array Sequence Analysis; Pancreatic Neoplasms; Phenols; Piperazines; Protein-Tyrosine Kinases; Pyrimidines; Quinones; Receptor, EphB3; Rifabutin

Src family tyrosine kinases participate in the regulation of cell adhesion, cell growth and differentiation. Here, we examine for the first time the potential role of Src for growth regulation of human pancreatic carcinoma cells. By immunohistochemical analysis, Src was overexpressed in 13/13 pancreatic carcinoma tissue but not in 6 normal pancreatic tissue specimen. In Western blots of total cellular extracts, Src protein expression was elevated in 14/17 carcinoma cell lines as compared to normal pancreas or cultured human pancreatic duct cells. Kinase activity was only detectable in cancer cells and did not correlate with the amount of kinase protein or with the expression of the regulatory kinase Csk, indicating that Src is not regulated through protein expression or through expression of Csk. The Src-specific tyrosine kinase inhibitor herbimycin A decreased cell growth in a dose-dependent manner. We suggest that Src family kinases participate in growth regulation of pancreatic cancer cells.

Topics: Aged; Benzoquinones; Cell Division; CSK Tyrosine-Protein Kinase; Enzyme Activation; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Lactams, Macrocyclic; Middle Aged; Neoplasm Staging; Pancreatic Neoplasms; Protein-Tyrosine Kinases; Proto-Oncogene Proteins pp60(c-src); Quinones; Rifabutin; src-Family Kinases; Tumor Cells, Cultured