Effect of celecoxib and cisplatin combination on apoptosis and cell proliferation in a mouse model of chemically-induced colonic aberrant crypt foci

The use of cisplatin for the treatment of cancer is accompanied by dose-dependent adverse effects. In colorectal cancer, there is upregulation of cyclooxygenase-2 (COX-2) expression increases prostaglandin E2 (PGE2) which in turn depresses apoptosis and potentiates invasion, angiogenesis, cell-proliferation and metastasis. This study investigates a possible synergistic function for celecoxib in cisplatin-based chemotherapy against chemically-induced colon carcinogenesis in mice. Mice received fifteen injections of 1,2-dimethylhydrazine dihydrochloride (DMH; 20 mg/kg/week, s.c.) to induce colon carcinogenesis and the normal control group received equal volumes of normal saline. Mice were randomly divided into five groups, (I) normal control group, (II) DMH control group (III) DMH + cisplatin (4 mg/kg/week, i.p.) group, (IV) DMH + celecoxib (10 mg/kg/day by gavage) group and (V) DMH + cisplatin + celecoxib group. Drugs were administered starting from week eleven until the end of the experiment (week 15). Colon specimens were used to evaluate histological grades, examine intratumoral expression of Bcl2, BAX and caspase-3 and the number of proliferating nuclei. The combination of cisplatin and celecoxib was effective against malignant transformation in mice with DMH-induced colonic aberrant crypt foci (ACF). The combination group showed improvement in histological grading, the highest caspase-3 expression and the lowest Bcl2/BAX ratio and reduction by approximately 50% of immunoreactivity for proliferating cell nuclear antigen (PCNA) compared to DMH control group. Addition of celecoxib to cisplatin regimen promotes apoptosis, suppresses tumor proliferation and augments the antitumor effect of cisplatin chemotherapy in the mouse model of DMH-induced ACF.