Abstract
Elucidation of the mechanism by which oxaliplatin induces cell death is essential to enhancing its action. We investigated the effects of oxaliplatin and 17-allylamino-17-demethoxygeldanamycin (17-AAG) in a panel of four colon adenocarcinoma cell lines. Cytotoxicity assays demonstrated at least additivity in three of the cell lines. Activation of the c-Jun NH(2)-terminal kinase pathway by oxaliplatin does not determine cytotoxicity. Activation of p38 was shown to be a key proapoptotic mediator of oxaliplatin-induced cell death. Modulation of extracellular signal-regulated kinase and AKT signaling had no impact on oxaliplatin toxicity in these cells. Nuclear factor (NF)-kappaB was constitutively active in all of the cell lines and was inhibited by 17-AAG. Down-regulation of NF-kappaB transactivation by pharmacological inhibitors enhanced oxaliplatin cytotoxicity. These data support an interaction between 17-AAG and components of the NF-kappaB pathway in the modulation of oxaliplatin sensitivity in colon cancer cells.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenocarcinoma / drug therapy*
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Adenocarcinoma / enzymology
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Adenocarcinoma / genetics
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Adenocarcinoma / pathology
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Benzoquinones
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Cell Death / drug effects
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Colonic Neoplasms / drug therapy*
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Colonic Neoplasms / enzymology
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Colonic Neoplasms / genetics
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Colonic Neoplasms / pathology
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Drug Synergism
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HCT116 Cells
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HT29 Cells
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Humans
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JNK Mitogen-Activated Protein Kinases*
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Lactams, Macrocyclic
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MAP Kinase Kinase 4
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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NF-kappa B / antagonists & inhibitors*
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NF-kappa B / physiology
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Organoplatinum Compounds / administration & dosage
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Oxaliplatin
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-raf / antagonists & inhibitors
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Proto-Oncogene Proteins c-raf / metabolism
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Rifabutin / administration & dosage
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Rifabutin / analogs & derivatives*
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Signal Transduction / drug effects
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Transcriptional Activation / drug effects
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p38 Mitogen-Activated Protein Kinases
Substances
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Benzoquinones
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Lactams, Macrocyclic
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NF-kappa B
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Organoplatinum Compounds
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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Oxaliplatin
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Rifabutin
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tanespimycin
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-raf
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4
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Mitogen-Activated Protein Kinase Kinases