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Experimental Therapeutics |
Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262 [P. L. R., D. J. A.], and Department of Veterans Affairs Medical Center, Denver, Colorado 80220 [P. L. R., R. J. G., E. C. R., L. J. D., D. J. A.]
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 µM) 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 µM) resulted in a time- and dose-dependent inhibition of ERK1/2 phosphorylation, and induction of apoptosis. U0126 treatment (20 µM) 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.
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