Pitavastatin suppresses diethylnitrosamine-induced liver preneoplasms in male C57BL/KsJ-db/db obese mice.

Abstract

BACKGROUND:

Obesity and related metabolic abnormalities, including inflammation and lipid accumulation in the liver, play a role in liver carcinogenesis. Adipocytokine imbalances, such as decreased serum adiponectin levels, are also involved in obesity-related liver tumorigenesis. In the present study, we examined the effects of pitavastatin - a drug used for the treatment of hyperlipidemia - on the development of diethylnitrosamine (DEN)-induced liver preneoplastic lesions in C57BL/KsJ-db/db (db/db) obese mice.

METHODS:

Male db/db mice were administered tap water containing 40 ppm DEN for 2 weeks and were subsequently fed a diet containing 1 ppm or 10 ppm pitavastatin for 14 weeks.

RESULTS:

At sacrifice, feeding with 10 ppm pitavastatin significantly inhibited the development of hepatic premalignant lesions, foci of cellular alteration, as compared to that in the untreated group by inducing apoptosis, but inhibiting cell proliferation. Pitavastatin improved liver steatosis and activated the AMPK-α protein in the liver. It also decreased free fatty acid and aminotransferases levels, while increasing adiponectin levels in the serum. The serum levels of tumor necrosis factor (TNF)-α and the expression of TNF-α and interleukin-6 mRNAs in the liver were decreased by pitavastatin treatment, suggesting attenuation of the chronic inflammation induced by excess fat deposition.

CONCLUSIONS:

Pitavastatin is effective in inhibiting the early phase of obesity-related liver tumorigenesis and, therefore, may be useful in the chemoprevention of liver cancer in obese individuals.

• Authors: Masahito Shimizu, Yoichi Yasuda, Hiroyasu Sakai, Masaya Kubota, Daishi Terakura, Atsushi Baba, Tomohiko Ohno, Takahiro Kochi, Hisashi Tsurumi, Takuji Tanaka, Hisataka Moriwaki
• Journal: BMC cancer (BMC Cancer) Vol. 11 Pg. 281 (Jun 28 2011) ISSN: 1471-2407 [Electronic] England
• PMID: 21711565 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adiponectin
• Adipoq protein, mouse
• Bad protein, mouse
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Interleukin-6
• Leptin
• Lipids
• Proto-Oncogene Proteins c-bcl-2
• Quinolines
• Tumor Necrosis Factor-alpha
• bcl-Associated Death Protein
• Diethylnitrosamine
• AMPK alpha1 subunit, mouse
• AMP-Activated Protein Kinases
• pitavastatin

Topics

• AMP-Activated Protein Kinases (drug effects)
• Adiponectin (blood)
• Animals
• Apoptosis (drug effects)
• Cocarcinogenesis
• Crosses, Genetic
• Diethylnitrosamine (toxicity)
• Drug Screening Assays, Antitumor
• Dyslipidemias (blood, complications, drug therapy, genetics)
• Fatty Liver (drug therapy, etiology)
• Gene Expression Regulation (drug effects)
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (therapeutic use)
• Interleukin-6 (biosynthesis, genetics)
• Leptin (blood)
• Lipids (blood)
• Liver (drug effects, metabolism, pathology)
• Liver Diseases (etiology, pathology, prevention & control)
• Liver Neoplasms, Experimental (chemically induced, prevention & control)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Obese
• Obesity (blood, complications, genetics)
• Organ Size (drug effects)
• Precancerous Conditions (chemically induced, pathology, prevention & control)
• Proto-Oncogene Proteins c-bcl-2 (biosynthesis, genetics)
• Quinolines (therapeutic use)
• Tumor Necrosis Factor-alpha (biosynthesis, genetics)
• bcl-Associated Death Protein (biosynthesis, genetics)