title: Combination of atorvastatin with sulindac or naproxen profoundly inhibits colonic adenocarcinomas by suppressing the p65/β-catenin/cyclin D1 signaling pathway in rats.
abstract: Evidence supports the protective role of nonsteroidal anti-inflammatory drugs (NSAID) and statins against colon cancer. Experiments were designed to evaluate the efficacies atorvastatin and NSAIDs administered individually and in combination against colon tumor formation. F344 rats were fed AIN-76A diet, and colon tumors were induced with azoxymethane. One week after the second azoxymethane treatment, groups of rats were fed diets containing atorvastatin (200 ppm), sulindac (100 ppm), naproxen (150 ppm), or their combinations with low-dose atorvastatin (100 ppm) for 45 weeks. Administration of atorvastatin at 200 ppm significantly suppressed both adenocarcinoma incidence (52% reduction, P = 0.005) and multiplicity (58% reduction, P = 0.008). Most importantly, colon tumor multiplicities were profoundly decreased (80%-85% reduction, P < 0.0001) when given low-dose atorvastatin with either sulindac or naproxen. Also, a significant inhibition of colon tumor incidence was observed when given a low-dose atorvastatin with either sulindac (P = 0.001) or naproxen (P = 0.0005). Proliferation markers, proliferating cell nuclear antigen, cyclin D1, and β-catenin in tumors of rats exposed to sulindac, naproxen, atorvastatin, and/or combinations showed a significant suppression. Importantly, colon adenocarcinomas from atorvastatin and NSAIDs fed animals showed reduced key inflammatory markers, inducible nitric oxide synthase and COX-2, phospho-p65, as well as inflammatory cytokines, TNF-α, interleukin (IL)-1β, and IL-4. Overall, this is the first report on the combination treatment using low-dose atorvastatin with either low-dose sulindac or naproxen, which greatly suppress the colon adenocarcinoma incidence and multiplicity. Our results suggest that low-dose atorvastatin with sulindac or naproxen might potentially be useful combinations for colon cancer prevention in humans.
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA.
authors.forename: Nanjoo
authors.initials: N
authors.lastname: Suh
authors.forename: Bandaru S
authors.initials: BS
authors.lastname: Reddy
authors.forename: Andrew
authors.initials: A
authors.lastname: DeCastro
authors.forename: Shiby
authors.initials: S
authors.lastname: Paul
authors.forename: Hong Jin
authors.initials: HJ
authors.lastname: Lee
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Smolarek
authors.forename: Jae Young
authors.initials: JY
authors.lastname: So
authors.forename: Barbara
authors.initials: B
authors.lastname: Simi
authors.forename: Chung Xiou
authors.initials: CX
authors.lastname: Wang
authors.forename: Naveena B
authors.initials: NB
authors.lastname: Janakiram
authors.forename: Vernon
authors.initials: V
authors.lastname: Steele
authors.forename: Chinthalapally V
authors.initials: CV
authors.lastname: Rao
mesh_terms: D000230:Adenocarcinoma / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069059:Atorvastatin; D001397:Azoxymethane / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D019938:Cyclin D1 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006538:Heptanoic Acids / Q000627:therapeutic use*; D007124:Immunoenzyme Techniques; D015847:Interleukin-4 / Q000378:metabolism; D008297:Male; D009288:Naproxen / Q000627:therapeutic use*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011758:Pyrroles / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000187:drug effects*; D013467:Sulindac / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000924:Anticholesteremic Agents; D002273:Carcinogens; D006538:Heptanoic Acids; D011758:Pyrroles; D014409:Tumor Necrosis Factor-alpha; D051176:beta Catenin; D019938:Cyclin D1; D013467:Sulindac; D015847:Interleukin-4; D009288:Naproxen; D000069059:Atorvastatin; D052247:Nitric Oxide Synthase Type II; D019892:eIF-2 Kinase; D001397:Azoxymethane