pitavastatin and Colonic-Neoplasms

Previous studies have demonstrated the importance of stem cells in human cancer, including colon cancer. Pitavastatin is approved for the treatment of hyperlipidemia and has also been shown to inhibit stem cell proliferation in preliminary in vitro studies. This study was done to investigate the effects of pitavastatin on human colon carcinoma stem cells (coCSCs) in vitro and in mouse tumor xenografts in vivo.. Human colon adenocarcinoma cell lines, SW480 and SW620, were cultured to the spheroid formation. The effects of pitavastatin on colon cancer stem cells were studied using the colorimetric MTT cell proliferation assay; quantitative polymerase chain reaction was used to determine the expression of cell cycle genes, OCT4, SOX2, and NANOG; Western blots were performed to measure MDR1. Mice were injected subcutaneously with SW480 cells; the growth of these tumor xenografts was studied using volumetric analysis following pitavastatin treatment.. Specific cell culture medium provided conditions that resulted in the expression of colon cancer stem cell markers when compared with normal cultured cells. Colon cancer stem cells were inhibited by pitavastatin treatment. Pitavastatin reduced the expression of stem cell markers of colon cancer stem cells and induced the cell apoptosis. Pitavastatin inhibited the growth of mouse tumor xenografts.. The findings of this preliminary study have demonstrated a potential role for pitavastatin in the inhibition of stem cell proliferation in colon carcinoma. Further studies are recommended to determine the mechanism of these effects on colon carcinoma cells in vitro and in vivo.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Humans; Mice; Neoplastic Stem Cells; Quinolines; Xenograft Model Antitumor Assays

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, beta-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-alpha (TNF-alpha), 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-alpha, 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.

Topics: Animals; Azoxymethane; Carcinogens; Cell Division; Colonic Neoplasms; Cytokines; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Precancerous Conditions; Quinolines

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are known to modulate carcinogenesis. In this study, we investigated whether a lipophilic HMG-CoA reductase inhibitor pitavastatin suppresses inflammation-related mouse colon carcinogenesis. Male CD-1 (ICR) mice were initiated with a single intraperitoneal injection of azoxymethane (AOM, 10 mg/kg body weight) and promoted by 2% (w/v) dextran sodium sulfate (DSS) in drinking water for 7 days. The experimental diets containing pitavastatin at 2 dose levels (1 and 10 ppm) were fed to male CD-1 (ICR) mice for 17 weeks, staring 1 week after the cessation of DSS exposure. The effects of dietary pitavastatin on colonic tumor development were assessed at Weeks 5, 10 and 20. Feeding with pitavastatin at both doses significantly inhibited the multiplicity of colonic adenocarcinoma at Week 20. Furthermore, the treatment significantly lowered the positive rates of proliferating cell nuclear antigen and increased the apoptotic index in the colonic epithelial malignancies. The treatment also reduced nitrotyrosine-positivity in the colonic mucosa. Our findings thus show that pitavastatin is effective in inhibiting colitis-related colon carcinogenesis through modulation of mucosal inflammation, oxidative/nitrosative stress, and cell proliferation.

Topics: Animals; Body Weight; Cholesterol; Colonic Neoplasms; DNA, Single-Stranded; Immunohistochemistry; Inflammation; Male; Mice; Molecular Structure; Organ Size; Proliferating Cell Nuclear Antigen; Quinolines; Time Factors; Triglycerides; Tyrosine