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Celecoxib and Curcumin Synergistically Inhibit the Growth of Colorectal Cancer Cells

Authors' Affiliations: ¹ Department of Cancer Prevention, Tel Aviv Medical Center; ² Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and ³ Institute of Cancer Research, Wien University, Vienna, Austria

Requests for reprints: Nadir Arber, Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel. Phone: 972-3-6974968; Fax: 972-3-6950339; E-mail: nadir{at}tasmc.health.gov.il or narber{at}post.tau.ac.il.

Purpose: Multiple studies have indicated that cyclooxygenase-2 (COX-2) inhibitors may prevent colon cancer, which is one of the leading causes of cancer death in the western world. Recent studies, however, showed that their long-term use may be limited due to cardiovascular toxicity. This study aims to investigate whether curcumin potentiates the growth inhibitory effect of celecoxib, a specific COX-2 inhibitor, in human colon cancer cells.

Experimental Design: HT-29 and IEC-18-K-ras (expressing high levels of COX-2), Caco-2 (expressing low level of COX-2), and SW-480 (no expression of COX-2) cell lines were exposed to different concentrations of celecoxib (0-50 µmol/L), curcumin (0-20 µmol/L), and their combination. COX-2 activity was assessed by measuring prostaglandin E₂ production by enzyme-linked immunoassay. COX-2 mRNA levels were assessed by reverse transcription-PCR.

Results: Exposure to curcumin (10-15 µmol/L) and physiologic doses of celecoxib (5 µmol/L) resulted in a synergistic inhibitory effect on cell growth. Growth inhibition was associated with inhibition of proliferation and induction of apoptosis. Curcumin augmented celecoxib inhibition of prostaglandin E₂ synthesis. The drugs synergistically down-regulated COX-2 mRNA expression. Western blot analysis showed that the level of COX-1 was not altered by treatment with celecoxib, curcumin, or their combination.

Conclusions: Curcumin potentiates the growth inhibitory effect of celecoxib by shifting the dose-response curve to the left. The synergistic growth inhibitory effect was mediated through a mechanism that probably involves inhibition of the COX-2 pathway and may involve other non–COX-2 pathways. This synergistic effect is clinically important because it can be achieved in the serum of patients receiving standard anti-inflammatory or antineoplastic dosages of celecoxib.

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