ABSTRACT
BACKGROUND: Resistance in apoptosis by disruption in signaling pathways is a common trait in malignancy. Celecoxib, a specific COX-2 inhibitor, has been reported to exert chemopreventive effect by inducing apoptosis. However, high doses or chronic usage of celecoxib for longer periods have various side effects. n-3 PUFA rich fish oil also abrogates COX-2 expression in tumors and thereby, has chemopreventive action. Combinatorial strategy using these two has been reported to be beneficial in mammary carcinoma. The present study was designed to understand the role of intrinsic and extrinsic apoptotic pathways in chemopreventive effect of celecoxib and fish oil in the initial phases of mammary carcinogenesis. METHODS: Female Wistar rats were distributed into control and DMBA treated groups and further subdivided based on pretreatment with celecoxib and/or fish oil. The animals were subsequently maintained for 90 days and then sacrificed. The proteins involved in intrinsic and extrinsic pathways were assessed in isolated mammary epithelial cells using flowcytometry. RESULTS: An increase in Bax, Bcl-2, Fas, FasL and caspase 8 levels was observed in DMBA treated animals. Celecoxib and/or fish oil further upregulate Bax, Fas, Fas L and caspase-8 while Bcl-2 levels were decreased. However maximal effect was observed with combinatorial dose of celecoxib and fish oil regimen. CONCLUSION: Administration of a combinatorial therapy of fish oil and celecoxib in mammary carcinoma exert better chemopreventive effect by modulation of both intrinsic and extrinsic apoptotic pathways.
Subject(s)
Apoptosis/drug effects , Carcinogenesis/pathology , Celecoxib/pharmacology , Fish Oils/pharmacology , Mammary Neoplasms, Animal/pathology , Mammary Neoplasms, Experimental/pathology , Signal Transduction/drug effects , 9,10-Dimethyl-1,2-benzanthracene , Animals , Carcinogenesis/drug effects , Caspase 8/metabolism , Cell Separation , Cytochromes c/metabolism , Epithelial Cells/drug effects , Epithelial Cells/enzymology , Epithelial Cells/metabolism , Fas Ligand Protein/metabolism , Female , Mammary Neoplasms, Animal/metabolism , Mammary Neoplasms, Experimental/metabolism , Membrane Potential, Mitochondrial/drug effects , Rats, Wistar , bcl-2-Associated X Protein/metabolism , fas Receptor/metabolismABSTRACT
Chronic inflammation has been directly linked to cancer progression. Therefore, current study was designed to understand the mechanism of action of chemo-preventive effect of celecoxib and fish oil on inflammatory mediators in experimental mammary carcinoma. Female Wistar rats were distributed into control and DMBA treated groups and further subdivided based on pretreatment with celecoxib and/or fish oil. Inflammation was measured by assessing expression of NF-κB, COX-2 and cytokines. The results indicated an elevation in expression of NF-κB, COX-2 and cytokines' levels (IFN-γ, IL-4 and IL-10) in DMBA group as compared to controls. On pretreatment with celecoxib and/or fish oil in DMBA treated animals, a significant reduction in expression of NF-κB, COX-2 and cytokines' levels was observed. The decrease was more pronounced with combinatorial regimen than either celecoxib or fish oil alone. To conclude, a combinatorial strategy of celecoxib and fish oil may generate an immune response against the tumor cell by altering cytokine repertoire and decrease the tendency of tumor cells to escape immune surveillance.
Subject(s)
Celecoxib/administration & dosage , Fish Oils/administration & dosage , Inflammation/drug therapy , Mammary Neoplasms, Experimental/prevention & control , Animals , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/pharmacology , Celecoxib/pharmacology , Cyclooxygenase 2/drug effects , Cyclooxygenase 2/metabolism , Cyclooxygenase 2 Inhibitors/administration & dosage , Cytokines/metabolism , Drug Therapy, Combination , Female , Fish Oils/pharmacology , Inflammation/complications , Inflammation Mediators/metabolism , NF-kappa B/metabolism , Rats , Rats, WistarABSTRACT
n-3 Polyunsaturated fatty acids (PUFA) have a chemopreventive effect while n-6 PUFA promote carcinogenesis. The effect of these essential fatty acids may be related to oxidative stress. Therefore, the study was designed to evaluate the effect of different ratios of fish oil (FO) and corn oil (CO) in the prevention of colon cancer. Male Wistar rats were divided into control, dimethylhydrazine dihydrochloride (DMH) treated, FO + CO (1:1) and FO + CO (2.5:1). All the groups, except the control received a weekly injection of DMH for 4 weeks. The animals were sacrificed either 48 h later (initiation phase) or kept for 16 weeks (post initiation phase). DMH treatment in the initiation phase animals showed mild to moderate inflammation, decreased ROS and TrxR activity, increased antioxidants, apoptosis and ACF multiplicity. The post initiation study showed severe inflammation with hyperplasia, increased ACF multiplicity and ROS levels, a decrease in antioxidants and apoptosis. The FO + CO (1:1) treated animals showed severe inflammation, a decrease in ROS, an increase in antioxidants and apoptosis in the initiation phase. FO + CO (1:1) in the post initiation phase and FO + CO (2.5:1) in the initiation showed mild inflammation, increased ROS, apoptosis and decreased antioxidants. There was a decrease in ACF multiplicity and ROS levels, increased antioxidants and apoptosis in the post initiation phase study. The present study suggests that FO has a dose- and time-dependent chemopreventive effect in colon cancer mediated through oxidative stress and apoptosis.
