J Korean Soc Coloproctol.  2005 Jun;21(3):121-128.

Adjuvant Effect of NSAIDs on the Cytotoxicity of Colon Cancer Cells to 5-FU

• Lee TB
• Kim KJ
• Min YD
• Kang SI
• Jung KR
• Lee JU
• Choi CH

Abstract

PURPOSE: Cyclooxygenase (COX)-2, an inducible enzyme that catalyzes the conversion of arachidonic acid to prostaglandins, is believed to be an important enzyme related to colorectal cancer. A large number of studies have supported the concept that non-steroidal anti-inflammatory drugs (NSAIDs) targeting COX alter the biologic processes of colon carcinogenesis. Although COX-2 inhibitors generally reduce the growth rate of established tumors, tumor regression is rarely observed. Hence, it is reasonable that COX-2 inhibitors be given in conjunction with standard anti-cancer therapy in treating cancer. We investigated whether aspirin and meloxicam not only are cytotoxic but also potentiate the antitumor effect of 5-Fluorouracil (5-FU) against colon cancer cells.
METHODS
Expressions of COX-1 and COX-2 were determined by using the reverse transcriptase-polymerase chain reaction (RT-PCR) & Western blotting assay in 9 colon cancer cell lines. The cytotoxicities of NSAIDs and/or 5-FU were determined by using a microculture tetrazolium dye (MTT) assay.
RESULTS
COX-1 mRNA and protein, as well as COX-2 mRNA, were variably expressed in all the cell lines tested whereas COX-2 protein was expressed in HT-29 and to a lesser extent in HCT-8, but not in the other cell lines. We selected two representative cell lines, HT-29 expressing COX-2 protein and SNU-C1 not expressing it. The dose-dependent cytotoxicity was observed in both cell lines treated with aspirin and with meloxicam. A combination treatment of aspirin or meloxicam with 5-FU revealed some additive effect, rather than a synergistic effect, for both cells lines. This additive effect was remarkable even for low concentrations of the drugs. Furthermore, the additive effect was highest when the combination was adminstered sequentially, 5-FU followed by aspirin or meloxicam, in both cell lines.
CONCLUSIONS
These results suggest that a combination therapy using NSAIDs and 5-FU might be useful in the treatment of colon cancer cells not expressing COX-2, as well as in colon cancer cells expressing COX-2.

Keyword

COX-2; NSAIDs; 5-FU; Additive effect; Colon cancer cells

MeSH Terms

Anti-Inflammatory Agents, Non-Steroidal*
Arachidonic Acid
Aspirin
Blotting, Western
Carcinogenesis
Cell Line
Colon*
Colonic Neoplasms*
Colorectal Neoplasms
Cyclooxygenase 2 Inhibitors
Fluorouracil*
Prostaglandin-Endoperoxide Synthases
Prostaglandins
RNA, Messenger
Anti-Inflammatory Agents, Non-Steroidal
Arachidonic Acid
Aspirin
Cyclooxygenase 2 Inhibitors
Fluorouracil
Prostaglandin-Endoperoxide Synthases
Prostaglandins
RNA, Messenger