title: Paradoxical and contradictory effects of imatinib in two cell line models of hormone-refractory prostate cancer.
abstract: BACKGROUND
  Imatinib mesylate is a chemotherapeutic drug that inhibits the tyrosine kinase activity of c-KIT and has been successfully used to treat leukemias and some solid tumors. However, its application for treatment of hormone-refractory prostate cancer (HRPC) has shown modest effectiveness and did not follow the outcomes in cultured cells or animal models. Moreover, the molecular pathways by which imatinib induces cytotoxicity in prostate cancer cells are poorly characterized.
  
  
  METHODS
  Two cell line models of HRPC (DU145 and PC3) were exposed to 20 μM of imatinib for 6-72 hr. MTS assay was used to assess cell viability during the course of experiment. Gene expression analysis of c-KIT, cell-cycle and apoptosis regulators, and angiogenic factors was determined by means of real-time PCR, western blot, and/or immunocytochemistry. The enzymatic activity of the apoptosis effector, caspase-3, was determined by a colorimetric assay.
  
  
  RESULTS
  Imatinib significantly decreased the viability of DU145 cells but paradoxically augmented the viability of PC3 cells. DU145 cells displayed diminished expression of anti-apoptotic Bcl-2 protein and augmented levels of caspase-8 and -9, as well as, increased enzymatic activity of caspase-3 in response to imatinib. No differences existed on the expression levels of apoptosis-related proteins in PC3 cells treated with imatinib, though the activity of caspase-3 was decreased. The mRNA levels of angiogenic factor VEGF were decreased in DU145-treated cells, whereas an opposite effect was seen in PC3. In addition, it was shown that DU145 and PC3 cells present a differential expression of c-KIT protein variants.
  
  
  CONCLUSIONS
  DU145 and PC3 cells displayed a contradictory behavior in response to imatinib, which was underpinned by a distinct expression pattern (or activity) of target regulators of cell-cycle, apoptosis, and angiogenesis. The paradoxical effect of imatinib in PC3 cells may be related with the differential expression of c-KIT protein variants. Moreover, the present findings helped to understand the discrepancies in the efficacy of imatinib as therapeutic option in HRPC.
authors: CICS-UBI, Health Sciences Research Center, University of Beira Interior, Covilhã, Portugal.
authors: Henrique J
authors: HJ
authors: Cardoso
authors: Cátia V
authors: CV
authors: Vaz
authors: Sara
authors: S
authors: Correia
authors: Marília I
authors: MI
authors: Figueira
authors: Ricardo
authors: R
authors: Marques
authors: Cláudio J
authors: CJ
authors: Maia
authors: Sílvia
authors: S
authors: Socorro
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics; D054462:p21-Activated Kinases / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D054462:p21-Activated Kinases; D020169:Caspases
keywords: DU145; PC3; c-KIT; hormone-refractory prostate cancer; imatinib; prostate cancer cells