Pitavastatin inhibits azoxymethane‐induced colonic preneoplastic lesions in C57BL/KsJ‐db/db obese mice

Abstract

Obesity and related metabolic abnormalities are risk factors for colorectal cancer. A state of chronic inflammation and adipocytokine imbalance may play a role in colorectal carcinogenesis. Statins, which are commonly used for the treatment of hyperlipidemia, are known to possess anti-inflammatory effects. Statins also exert chemopreventive properties against various cancers. The present study examined the effects of pitavastatin, a recently developed lipophilic statin, on the development of azoxymethane (AOM)-initiated colonic premalignant lesions in C57BL/KsJ-db/db (db/db) obese mice. Male db/db mice were administrated weekly subcutaneous injections of AOM (15 mg/kg body weight) for 4 weeks and then were subsequently fed a diet containing 1 ppm or 10 ppm pitavastatin for 8 weeks. Feeding with either dose of pitavastatin significantly reduced the number of colonic premalignant lesions, b-catenin accumulated crypts, by inhibiting proliferation and the surrounding inflammation. Pitavastatin increased the serum levels of adiponectin while conversely decreasing the serum levels of total cholesterol, tumor necrosis factor-a (TNF-a), interleukin (IL)-6, IL-18, and leptin. Pitavastatin also caused a significant increase in the expression of phosphorylated form of the AMP-activated kinase (AMPK) protein on the colonic mucosa of AOM-treated mice. In addition, the expression levels of TNF-a, IL-6, IL-18, and COX-2 mRNAs on the colonic mucosa of AOM-treated mice were decreased by treatment with this agent. These findings suggest that pitavastatin attenuates chronic inflammation and improves the imbalance of adipocytokines, both of which are caused by the presence of excess adipose tissues, thereby preventing the development of colonic premalignancies in an obesity-related colon cancer model. Therefore, some types of statins, including pitavastatin, may be a useful chemoprevention modality for colon cancer in obese individuals. (Cancer Sci

Acyclic Retinoid Inhibits Diethylnitrosamine-Induced Liver Tumorigenesis in Obese and Diabetic C57BLKS/J- +Leprdb/+Leprdb Mice

“…Dietary energy restriction suppresses mammary tumorigenesis in rats by increasing the levels of activated AMPK (45). Pitavastatin, a lipophilic statin, was found to prevent obesity-and diabetes-related colon carcinogenesis in mice by activating AMPK in the colonic mucosa (29). These reports suggest the possibility that activation of AMPK by ACR aided in suppressing the development of obesity-related liver cells adenomas, as observed in the present study.…”

“…Previously described primary antibodies for RXRa , ERK, phosphorylated ERK (p-ERK), Stat3, p-Stat3, AMP-activated kinase (AMPK), p-AMPK, and GAPDH were used (15,22,28,29). The DN-197 antibody is considered a specific antibody for the p-RXRa protein (22,23).…”

“…Before sacrifice, the mice were fasted for 6 hours, and at sacrifice, blood samples were collected for assaying the serum concentrations of insulin, glucose, and TNF-a, which was as described previously (4,29). The serum TNF-a (Shibayagi) levels were determined using an enzyme immunoassay according to the manufacturer's protocol.…”

Preventive Effects of (−)-Epigallocatechin Gallate on Diethylnitrosamine-Induced Liver Tumorigenesis in Obese and Diabetic C57BL/KsJ-db/db Mice

“…Previously described primary antibodies for IGF-1R, phosphorylated IGF-1R (p-IGF-1R), ERK, p-ERK, Akt, p-Akt, Stat3, p-Stat3, AMP-activated kinase (AMPK), p-AMPK, glycogen synthase kinase (GSK)-3b, p-GSK-3b, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were used (16,26,27). The primary antibody for c-Jun NH 2 -terminal kinase (JNK) and p-JNK was obtained from Cell Signaling Technology.…”

“…The cDNA was amplified from 0.2 mg of total RNA, using the SuperScript III First-Strand Synthesis System (Invitrogen). Quantitative real-time reverse transcriptase PCR (RT-PCR) analysis was done using specific primers that amplify the TNF-a, IL-6, IL-1b, IL-18, and b-actin genes, as described previously (26,28).…”