title: The efficacy of tyrosine kinase inhibitors on human pancreatic cancer cell lines.
abstract: 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.
authors.affiliation: Brigham and Women's Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Robert Saeid
authors.initials: RS
authors.lastname: Farivar
authors.forename: James
authors.initials: J
authors.lastname: Gardner-Thorpe
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Ito
authors.forename: Hassan
authors.initials: H
authors.lastname: Arshad
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Zinner
authors.forename: Stanley W
authors.initials: SW
authors.lastname: Ashley
authors.forename: Edward E
authors.initials: EE
authors.lastname: Whang
mesh_terms: D001549:Benzamides; D016227:Benzoquinones; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D000068877:Imatinib Mesylate; D047029:Lactams, Macrocyclic; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms; D010636:Phenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology; D011809:Quinones / Q000494:pharmacology; D036223:Receptor, EphB3 / Q000235:genetics; D017828:Rifabutin / Q000031:analogs & derivatives
chemical_list: D001549:Benzamides; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D047029:Lactams, Macrocyclic; D010636:Phenols; D010879:Piperazines; D011743:Pyrimidines; D011809:Quinones; D017828:Rifabutin; C062898:lavendustin A; C020754:herbimycin; D000068877:Imatinib Mesylate; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D036223:Receptor, EphB3