title: A protein kinase C inhibitor induces phenotypic reversion of ras-transformed pancreatic cancer cells and cooperatively blocks tumor cell proliferation with an anti- ras peptide.
abstract: OBJECTIVE
  We have previously found that the staurosporine derivative, CGP 41 251, that has a high specificity for inhibiting protein kinase C (PKC), selectively blocks oncogenic ras-p21-induced oocyte maturation and that PKC and jun-N-terminal kinase (JNK), with which oncogenic ras-p21 directly interacts, reciprocally require each other's activation. We sought to determine whether CGP 41 251 blocks proliferation of ras-transformed mammalian cells and whether it synergistically exerts this effect with a ras-p21 peptide (residues 96-110) that interferes with the interaction of ras-p21 with JNK.
  
  
  METHODS
  We incubated ras-transformed rat pancreatic cancer TUC-3 cells and their normal counterpart pancreatic acinar BMRPA1 cells with CGP 42 251 alone and in the presence of the ras-p21 96-110 peptide, both in pre- and post-monolayer phases and determined cell counts and morphology and, for TUC-3 cells, their ability to grow on soft agar. In the post-monolayer experiments, we also evaluated these parameters after withdrawal of these agents.
  
  
  RESULTS
  CGP 41 251, but not its inactive analogue, CGP 42 700, blocked pre-monolayer growth and reduced post-monolayer cell counts of both TUC-3 and BMRPA1 cells (IC(50) 0.28 and 0.35 micro M, respectively). After 2 weeks of treatment, all the remaining TUC-3 cells exhibited the untransformed phenotype. Withdrawal of CGP 41 251 resulted in almost complete regrowth of the normal BMRPA1 cells while the reverted TUC-3 cells grew much more slowly. These effects were greatly enhanced by the presence of the ras-p21 96-110 peptide.
  
  
  CONCLUSIONS
  CGP 41 251 strongly blocks growth of ras-transformed pancreatic cancer cells by causing cell death and by induction of phenotypic reversion. The enhancement of this effect by the ras-p21 96-110 peptide indicated synergy between it and CGP 41 251, allowing it to block proliferation of the transformed cells selectively. These findings suggest the possibility of using these two agents in anticancer therapy.
authors.affiliation: Department of Biology, Long Island University, Brooklyn, NY 11201, USA.
authors.forename: Denise
authors.initials: D
authors.lastname: Way
authors.forename: Steven
authors.initials: S
authors.lastname: Smith
authors.forename: Sharmila
authors.initials: S
authors.lastname: Sivendran
authors.forename: Lyndon
authors.initials: L
authors.lastname: Chie
authors.forename: Mecheal
authors.initials: M
authors.lastname: Kanovsky
authors.forename: Paul W
authors.initials: PW
authors.lastname: Brandt-Rauf
authors.forename: Denise L
authors.initials: DL
authors.lastname: Chung
authors.forename: Josef
authors.initials: J
authors.lastname: Michl
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Pincus
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D018267:Carcinoma, Acinar Cell / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D015689:Oncogene Protein p21(ras) / Q000037:antagonists & inhibitors / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D010641:Phenotype; D011485:Protein Binding; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction; D019311:Staurosporine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D015689:Oncogene Protein p21(ras); D019311:Staurosporine; C059539:midostaurin