Abstract A146: Meloxicam inhibits prostate tumor growth and progression in prostate specific-PTEN conditional gene targeting knockout mice

Abstract

Abstract A high incidence of prostate cancer in older men suggests that agents that inhibit or delay the disease process could be beneficial in reducing cancer mortality and morbidity. Increased expression of COX-2 has been found in most of the cancers and compelling evidence from genetic and clinical studies indicates that COX-2 upregulation is one of the key steps in carcinogenesis. There is a strong body of evidence pointing out the role of COX-2 early in the prostate carcinogenesis process, particularly in the progression of prostatic intraepithelial neoplasia (PIN) lesions to prostate carcinoma. Epidemiological data suggests that treatments with non-steroidal anti-inflammatory drugs (NSAIDs) were associated with reduced risk in a number of malignancies. We evaluated the chemopreventive efficacy of meloxicam, a selective COX-2 inhibitor, against prostate cancer in prostate-specific PTEN knockout mice. In our mouse model, homozygous inactivation of PTEN leads to PIN at 8 weeks of age with 50% of the mice progressing to prostate cancer by the age of 10 weeks and 100% by 20 weeks of age. Mice were fed meloxicam (3.0 mg/l ad libitum) in drinking water beginning at 4 or 11 weeks of age for 5 to 28 weeks in stage-specific manners. There were no bodyweight differences were seen between treatment groups. Our data showed a significant reduction (19–23%, p<0.05) of genitourinary tract weights in meloxicam-fed mice. There was a strong reduction in the incidence and extent of adenocarcinoma and increases in PIN in meloxicam-fed mice. Significant differences in tumor differentiation scores were also noted in the treatment groups (p<0.05). Immunohistochemical analysis revealed that meloxicam treatment did in fact reduce COX-2 expression without inhibiting COX-1. Furthermore, meloxicam-fed mice also showed reduced proliferation rates as well as increases in apoptotic rates. Moreover, a reduction of VEGF expression in tumors and tumor stroma was also observed in mice treated with meloxicam. These results suggest that meloxicam safely inhibited tumor growth and progression in the PTEN knockout mouse model by antiproliferative, pro-apoptotic and anti-angiogenic effects and may thus be a suitable candidate for use in human chemoprevention trials. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A146.