Inhibition of extracellular signal-regulated kinase 1/2 phosphorylation and induction of apoptosis by sulindac metabolites

• Published in: Cancer research (Chicago, Ill.) Vol. 61; no. 4; pp. 1541 - 1547
• Main Authors: RICE, Pamela L, GOLDBERG, Ryan J, RAY, Evan C, DRIGGERS, Linda J, AHNEN, Dennis J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-02-2001
• Subjects: 3',5'-Cyclic-GMP Phosphodiesterases - antagonists & inhibitors; 3',5'-Cyclic-GMP Phosphodiesterases - metabolism; Anti-Inflammatory Agents, Non-Steroidal - metabolism; Antineoplastic agents; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Apoptosis - physiology; Biological and medical sciences; Butadienes - pharmacology; Caspase 3; Caspase 7; Caspases - metabolism; Colonic Neoplasms - enzymology; Colonic Neoplasms - pathology; Down-Regulation; Enzyme Activation; Enzyme Inhibitors - pharmacology; ERK1 kinase; ERK2 kinase; General aspects; Humans; MAP Kinase Kinase Kinase 1; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Medical sciences; Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 1 - biosynthesis; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - biosynthesis; Mitogen-Activated Protein Kinases - metabolism; Nitriles - pharmacology; Pharmacology. Drug treatments; Phosphorylation - drug effects; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; sulindac; Sulindac - analogs & derivatives; Sulindac - metabolism; Sulindac - pharmacology; Tumor Cells, Cultured - drug effects; Antineoplastic agent; Phosphorylation; Sulfone; Metabolite; Cysteine endopeptidases; Sulfides; Signal transduction; Sulindac; Established cell line; Intestinal disease; Indene derivatives; Colon; Mechanism of action; Human; Enzyme; Transferases; Malignant tumor; Acetic acid derivative; In vitro; Colonic disease; Peptidases; Cell death; Protein kinase; Digestive diseases; Hydrolases; Apoptosis
• ISSN: 0008-5472; 1538-7445

Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and sulindac is associated with a decreased mortality from colorectal cancer. Sulindac causes regression of precancerous adenomatous polyps and inhibits the growth of cultured colon cell lines. Whereas induction of apoptotic cell death is thought to account for the growth inhibitory effect of sulindac, less is known about its biochemical mechanism(s) of action. Sulindac is metabolized in vivo to sulfide and sulfone derivatives. Both the sulfide and sulfone metabolites of sulindac as well as more potent cyclic GMP-dependent phosphodiesterase inhibitors were shown to cause inhibition of extracellular signal-regulated kinase (ERK)1/2 phosphorylation at doses (40-600 microM) and times (1-5 days) consistent with the induction of apoptosis by the drugs. Treatment of HCT116 human colon cancer cells with the specific mitogen-activated protein kinase kinase, U0126 (5-50 microM) resulted in a time- and dose-dependent inhibition of ERK1/2 phosphorylation, and induction of apoptosis. U0126 treatment (20 microM) increased basal apoptosis, and potentiated the apoptotic effect of sulindac sulfide and sulindac sulfone. These results suggest that the inhibition of ERK1/2 phosphorylation is responsible for at least part of the induction of programmed cell death by sulindac metabolites. Inhibition of ERK1/2 activity may, therefore, be a useful biochemical target for the development of chemopreventive and chemotherapeutic drugs for human colon cancer.