title: Inhibition of JNK Sensitizes Hypoxic Colon Cancer Cells to DNA-Damaging Agents.
abstract: OBJECTIVE
  We showed previously that in HT29 colon cancer cells, modulation of hypoxia-induced stress signaling affects oxaliplatin cytotoxicity. To further study the significance of hypoxia-induced signaling through JNK, we set out to investigate how modulation of kinase activities influences cellular responses of hypoxic colon cancer cells to cytotoxic drugs.
  
  
  METHODS
  In a panel of cell lines, we investigated effects of pharmacologic and molecular inhibition of JNK on sensitivity to oxaliplatin, SN-38, and 5-FU. Combination studies for the drugs and JNK inhibitor CC-401 were carried out in vitro and in vivo.
  
  
  RESULTS
  Hypoxia-induced JNK activation was associated with resistance to oxaliplatin. CC-401 in combination with chemotherapy demonstrates synergism in colon cancer cell lines, although synergy is not always hypoxia specific. A more detailed analysis focused on HT29 and SW620 (responsive), and HCT116 (nonresponsive) lines. In HT29 and SW620 cells, CC-401 treatment results in greater DNA damage in the sensitive cells. In vivo, potentiation of bevacizumab, oxaliplatin, and the combination by JNK inhibition was confirmed in HT29-derived mouse xenografts, in which tumor growth delay was greater in the presence of CC-401. Finally, stable introduction of a dominant negative JNK1, but not JNK2, construct into HT29 cells rendered them more sensitive to oxaliplatin under hypoxia, suggesting differing input of JNK isoforms in cellular responses to chemotherapy.
  
  
  CONCLUSIONS
  These findings demonstrate that signaling through JNK is a determinant of response to therapy in colon cancer models, and support the testing of JNK inhibition to sensitize colon tumors in the clinic.
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. vasilevs@mail.med.upenn.edu.
authors.forename: Irina A
authors.initials: IA
authors.lastname: Vasilevskaya
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Muthu
authors.initials: M
authors.lastname: Selvakumaran
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Lucia Cabal
authors.initials: LC
authors.lastname: Hierro
authors.affiliation: Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Sara R
authors.initials: SR
authors.lastname: Goldstein
authors.affiliation: Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Winkler
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Dwyer
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004249:DNA Damage / Q000187:drug effects*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005799:Genes, Dominant; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D000077146:Irinotecan; D051379:Mice; D016513:Mice, SCID; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors* / Q000235:genetics*; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D047428:Protein Kinase Inhibitors / Q000737:chemistry; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D047428:Protein Kinase Inhibitors; D000077150:Oxaliplatin; D000077146:Irinotecan; D048055:Mitogen-Activated Protein Kinase 8; D005472:Fluorouracil; D002166:Camptothecin