Curcumin potentiates the growth-inhibitory effect of celecoxib in human colorectal cancer cells

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Background: Colorectal Cancer (CRC) is one of the leading causes of cancer death in the western world. Multiple studies have indicated that specific COX-2 inhibitors may prevent CRC. However, the long-term use of COX-2 inhibitors is not toxic free and may be limited due to its gastrointestinal and cardiovascular side effects. The chemopreventive efficacy of the phytochemical, curcumin has been demonstrated in several in vitro and animal models. We have developed a unique in vitro model consisting of normal rat emterocytes (IEC18) and their ras transformed derivatives (IEC18-ras) (Arber et al. Oncogene 1996). Aim: Can curcumin potentiate the growth inhibition effect of a COX-2 inhibitor (celecoxib, Pfizer, NY, USA) in human colon cancer cells? Methods: HT-29 and IEC18-ras (expressing high levels of COX -2), Caco-2 (Expressing low levels of COX-2) and SW-480 (no expression of COX -2) cell lines were exposed to different concentrations of celecoxib (0-40μM), curcumin (0-20μM) and their combination. COX-2 activity was assessed by measuring PGE₂ production by enzyme-linked immunoassay. COX-2 mRNA levels were assessed by RT-PCR. COX-1 and COX-2 expression was measured by western blotting analysis. Results:.Exposure to physiological doses of celecoxib (5 μM) and curcumin (10-15 μM) 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 PGE₂ 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 can potentiates the growth inhibitory effect of celecoxib by shifting the dose-response curve to the left. The synergistic growth inhibition effect was mediated through a mechanism that involves both COX-2 and non-COX-2 pathways. This synergistic effect is clinically important since it can be achieved in the serum of patients receiving standard anti-inflammatory or anti-neoplastic dosages of celecoxib.