Journal Article

Gene modulation by Cox-1 and Cox-2 specific inhibitors in human colorectal carcinoma cancer cells

Frank G. Bottone, Jeanelle M. Martinez, Brenda Alston-Mills and Thomas E. Eling

in Carcinogenesis

Volume 25, issue 3, pages 349-357
Published in print March 2004 | ISSN: 0143-3334
Published online March 2004 | e-ISSN: 1460-2180 | DOI:
Gene modulation by Cox-1 and Cox-2 specific inhibitors in human colorectal carcinoma cancer cells

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Cox-1 and Cox-2 specific inhibitors exert chemo-preventative activity. However, the exact mechanisms for this activity remain unclear. Increasing evidence suggests that non-steroidal anti-inflammatory drugs regulate gene expression, which may be responsible, in part, for this activity. In this study, human colorectal carcinoma HCT-116 cells were treated with the Cox-1 specific inhibitor SC-560 and the Cox-2 specific inhibitor SC-58125 to evaluate their ability to induce apoptosis, inhibit cell proliferation, inhibit growth on soft agar and modulate gene expression. The Cox-1 specific inhibitor, SC-560 significantly induced apoptosis and inhibited the growth of HCT-116 cells on soft agar, an in vitro assay for tumorigenicity. SC-58125 moderately induced apoptosis and inhibited growth on soft agar at higher concentrations than were required for SC-560. Previously, we reported that the potent chemo-preventative drug sulindac sulfide altered the expression of eight genes including several transcription factors that may be linked to this drug's chemo-preventative activity. HCT-116 cells were treated with various concentrations of SC-560 or SC-58125 and changes in the expression of these eight genes were determined by real-time reverse transcription– polymerase chain reaction. SC-560 modulated mRNA expression of the eight genes studied. In contrast, SC-58125 required ∼5–10-fold higher concentrations to achieve similar degrees of gene modulation in six of eight genes. Changes in protein expression by SC-560 also occurred for five of these genes with antibodies available (NAG-1, ATF3, C/EBPβ, MAD2 and MSX1). In conclusion, this is the first report to suggest that like sulindac sulfide, the Cox-1 specific inhibitor SC-560 appears to elicit chemo-preventative activity by altering gene expression, while the chemo-preventative effects of SC-58125 are complex and probably work through these and other mechanisms, such as the inhibition of Cox-2.

Keywords: ATF3, activating transcription factor 3; APC, adenomatous polyposis coli; Cox, cyclooxygenase; C/EBPβ, CCAAT/enhancer binding protein-β; FACS, fluorescence-activated cell sorting; NF-κB, nuclear factor-kappa B; FBS, fetal bovine serum; INSIG1, insulin induced gene 1; MSX1, Msh homeo box homolog 1; MAD2, mitotic arrest deficient-like 1; NAG-1, NSAID activated gene-1; NSAIDs, non-steroidal anti-inflammatory drugs; NRG-1, NSAID regulated gene-1; PGE2, prostaglandin E2; RT–PCR, reverse transcription–polymerase chain reaction; TBS-T, Tris-buffered saline Tween-20; VEGF, vascular endothelial growth factor

Journal Article.  6201 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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