Epidemiological studies have provided evidence that high intake of saturated fat and/or animal fat increases the risk of prostate cancer, but on the other hand, diets rich in omega-3 polyunsaturated fatty acids (n-3 PUFAs), present in fish oils were found to reduce the risk. There are indications of an increased expression of immunoreactive PPARgamma in prostatic intraepithelial neoplasia (PIN) and prostate cancer, suggesting that PPARgamma ligands may exert their own potent anti-proliferative effect against prostate cancer. The experimental evidence for the role of cyclooxygenase-2 (COX-2) in prostate carcinogenesis is well established through several investigations. It clearly suggests the need for development of strategies to inhibit COX-2 mediated prostate carcinogenesis. However, administration of high doses of COX-2 inhibitors, such as celecoxib, over longer periods may not be devoid of side effects. We assessed the efficacy of DHA and celecoxib individually and in combination at low doses in three prostate cancer cell lines (LNCaP, DU145 and PC-3) measuring cell growth inhibition and apoptosis, and on the levels of expression of COX-2, nuclear factor-kappaB (NF-kappaBp65), and nuclear receptors, such as PPARgamma and retinoid X receptors (RXR), all of which presumably participate in prostate carcinogenesis. A 48-h incubation of prostate cancer cells with 5 microM each of DHA or celecoxib induced cell growth inhibition and apoptosis, and altered the expression of the above molecular parameters. Interestingly, the modulation of these cellular and molecular parameters was more pronounced in cells treated with low doses of DHA and celecoxib (2.5 microM each) in combination than in cells treated with the higher doses of individual agents. In conclusion, the present study demonstrates for the first time that a combination of lower doses of the n-3 PUFA, and DHA with the selective COX-2 inhibitor celecoxib effectively modulates the above cellular and molecular parameters that are relevant to prostate cancer. This raises the intriguing prospect that the use of low doses of a COX-2 inhibitor in combination with an n-3 PUFA could be a highly promising strategy for prostate cancer chemoprevention while minimizing undesired side effects.