Cyclooxygenase-independent induction of p21(WAF-1/cip1), apoptosis and differentiation by L-745,337, a selective PGH synthase-2 inhibitor, and salicylate in HT-29 cells

G. Santini, M. G. Sciulli, R. Marinacci, O. Fusco, L. Spoletini, A. Pace, A. Ricciardulli, C. Natoli, A. Procopio, J. Maclouf, P. Patrignani

Research output: Contribution to journalArticle

Abstract

In order to dissect out cyclooxygenase-dependent from cyclooxygenase- independent mechanisms in the antiproliferative effects of selective prostaglandin H synthase (PGHS)-2 inhibitors, we compared the effects of L- 745,337 (a highly selective PGHS-2 inhibitor) with sodium salicylate (a weak PGHS inhibitor) on prostanoid production, induction of the cyclin-dependent kinase inhibitor p21(WAF-1/cip1), mutant p53 (m273-p53) levels, apoptosis and differentiation in human colon adenocarcinoma HT-29 cells. L-745,337 dose- dependently suppressed the cyclooxygenase activity of HT-29 cells (IC50:0.24 μM). Four-day treatment with L-745,337 caused a concentration- dependent inhibition of cell growth (IC50: 0.9 mM) associated with the induction of p21(WAF-1/cip1) and an increase in the proportion of apoptotic nuclei (EC50: 0.1 and 0.34 mM, respectively) while reducing the levels of m273-p53 (IC50: 0.2 mM). Sodium salicylate, at the concentration of 10 mM that did not affect prostanoid formation, caused a 60% reduction of cell growth associated with a 3-fold induction of p21(WAF-1/cip1) and a 60% increase in the proportion of apoptotic nuclei. Ultrastructural analysis showed that L-745,337 (0.5 mM) and sodium salicylate (10 mM) caused the induction of a differentiated phenotype. We conclude that high concentrations of L-745,337 and sodium salicylate inhibit colon cancer cell growth by a mechanism unrelated to cyclooxygenase inhibition that may involve p53- independent induction of the tumor suppressor p21(WAF-1/cip1).

Original languageEnglish
Pages (from-to)151-162
Number of pages12
JournalApoptosis
Volume4
Issue number3
DOIs
Publication statusPublished - 1999

Keywords

  • Apoptosis
  • Differentiation
  • HT-29 cells
  • L-745,337
  • p21(WAF-1/cip1)
  • Sodium salicylate

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Cell Biology

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    Santini, G., Sciulli, M. G., Marinacci, R., Fusco, O., Spoletini, L., Pace, A., Ricciardulli, A., Natoli, C., Procopio, A., Maclouf, J., & Patrignani, P. (1999). Cyclooxygenase-independent induction of p21(WAF-1/cip1), apoptosis and differentiation by L-745,337, a selective PGH synthase-2 inhibitor, and salicylate in HT-29 cells. Apoptosis, 4(3), 151-162. https://doi.org/10.1023/A:1009631204581