Statin-induced breast cancer cell death: role of inducible nitric oxide and arginase-dependent pathways.
نویسندگان
چکیده
Statins are widely used cholesterol-lowering drugs that selectively inhibit the enzyme 3-hydroxy-3-methylglutaryl CoA reductase, leading to decreased cholesterol biosynthesis. Emerging data indicate that statins stimulate apoptotic cell death in several types of proliferating tumor cells, including breast cancer cells, which is independent of its cholesterol-lowering property. The objective here was to elucidate the molecular mechanism(s) by which statins induce breast cancer cell death. Fluvastatin and simvastatin (5-10 mumol/L) treatment enhanced the caspase-3-like activity and DNA fragmentation in MCF-7 cells, and significantly inhibited the proliferation of MCF-7 cells but not MCF-10 cells (noncancerous epithelial cells). Statin-induced cytotoxic effects were reversed by mevalonate, an immediate metabolic product of the acetyl CoA/3-hydroxy-3-methylglutaryl CoA reductase reaction. Both simvastatin and fluvastatin enhanced nitric oxide ((.)NO) levels which were inhibited by mevalonate. Statin-induced (.)NO and tumor cell cytotoxicity were inhibited by 1400W, a more specific inhibitor of inducible nitric oxide synthase (iNOS or NOS II). Both fluvastatin and simvastatin increased iNOS mRNA and protein expression. Stimulation of iNOS by statins via inhibition of geranylgeranylation by GGTI-298, but not via inhibition of farnesylation by FTI-277, enhanced the proapoptotic effects of statins in MCF-7 cells. Statin-mediated antiproliferative and proapoptotic effects were exacerbated by sepiapterin, a precursor of tetrahydrobiopterin, an essential cofactor of (.)NO biosynthesis by NOS. We conclude that iNOS-mediated (.)NO is responsible in part for the proapoptotic, tumoricidal, and antiproliferative effects of statins in MCF-7 cells.
منابع مشابه
Arginase Activity and Its Effects on Pathogenesis of Leishmania
Leishmaniasis is a tropical parasitic disease that has become a major health challenge in many countries of the world. Not only has not been found any effective vaccine or treatment for the disease eradication, but also the advent of drug resistance is also increasing. Therefore, it is vital to take a precise attention to the physiochemical cycles of the Leishmania parasite and to identify i...
متن کاملEffect of 17-? Estradiol on the Expression of Inducible Nitric oxide Synthase in Parent and Tamoxifen Resistant T47D Breast Cancer Cells
Indirect evidence suggests that estrogen is involved in the etiology of breast cancer. Estrogen is also thought to modulate nitric oxide (NO) in human breast tumor tissue via regulation of inducible nitric oxide synthase (iNOS). Objectives of this study were to determine whether estradiol (E2) affects iNOS expression level in breast cancer cells and to study the effect of various concentrations...
متن کاملEffect of 17-? Estradiol on the Expression of Inducible Nitric oxide Synthase in Parent and Tamoxifen Resistant T47D Breast Cancer Cells
Indirect evidence suggests that estrogen is involved in the etiology of breast cancer. Estrogen is also thought to modulate nitric oxide (NO) in human breast tumor tissue via regulation of inducible nitric oxide synthase (iNOS). Objectives of this study were to determine whether estradiol (E2) affects iNOS expression level in breast cancer cells and to study the effect of various concentrations...
متن کاملEffect of Neutrophils on Nitric Oxide Production from Stimulated Macrophages
Background: During the initial phase of an infection, there is an upregulation of inducible nitric oxide synthase in the macrophages for the production of nitric oxide. This is followed by the recruitment of polymorphonuclear leukocytes (neutrophils) which release arginase. Arginase competes with inducible nitric oxide synthase for a common substrate L-arginine. Objective: To investigate whethe...
متن کاملEffects of lipopolysaccharide-induced septic shock on rat isolated kidney, possible role of nitric oxide and protein kinase C pathways
Objective(s): Pathophysiology of sepsis-associated renal failure (one of the most common cause of death in intensive care units) had not been fully determined. The effect of nitric oxide and protein kinase C (PKC) pathways in isolated kidney of Lipopolysaccharide-treated (LPS) rats were investigated in this study. Materials and Methods: Vascular responsiveness to phenylephrine and acetylcholine...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Cancer research
دوره 67 15 شماره
صفحات -
تاریخ انتشار 2007