The efficacy of tyrosine kinase inhibitors on human pancreatic cancer cell lines.
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.
Farivar
Robert Saeid
RS
Brigham and Women's Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02115, USA.
Gardner-Thorpe
James
J
Ito
Hiromichi
H
Arshad
Hassan
H
Zinner
Michael J
MJ
Ashley
Stanley W
SW
Whang
Edward E
EE
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
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