Differences in antitumor effects of various statins on human pancreatic cancer

Abstract

Statins are widely used for the treatment of hypercholesterolemia. However, their inhibitory action on HMG-CoA reductase also results in the depletion of intermediate biosynthetic products, which importantly contribute to cell proliferation. The aim of the present study was to compare the effects of the individual commercially available statins on experimental pancreatic cancer. The in vitro effects of individual statins (pravastatin, atorvastatin, simvastatin, lovastatin, cerivastatin, rosuvastatin and fluvastatin) on the viability of human pancreatic cancer were evaluated in CAPAN-2, BxPc-3 and MiaPaCa-2 cell lines. The in vivo experiments were performed on nude mice xenotransplanted with CAPAN-2 cells. The mice received oral treatments either with a placebo, or with the statins mentioned earlier in a daily dose corresponding to a hypocholesterolemic dose in humans. The effect of these statins on the intracellular Ras protein, trafficking in MiaPaCa-2 transfected cells, was also investigated. Substantial differences in the tumor-suppressive effects of all statins were detected in both in vitro and in vivo experiments. While simvastatin exerted the highest tumor-suppressive effects in vitro, rosuvastatin (p 5 0.002), cerivastatin (p 5 0.002) and fluvastatin (p 5 0.009) were the most potent compounds in an animal model. All statins (except pravastatin) inhibited intracellular Ras protein translocation. In summary, substantial tumor-suppressive effects of various statins on the progression of experimental pancreatic adenocarcinoma were demonstrated, with marked differences among individual statins. These results support greatly the potential of statins for the chemoadjuvant treatment of pancreatic cancer. ' 2007 Wiley-Liss, Inc.

Statins inhibit Akt/PKB signaling via P2X7 receptor in pancreatic cancer cells

“…Further, in Capan-2 cells, decreased levels of NFB and its downstream target, survivin, were induced by atorvastatin. These data suggest that under conditions used here atorvastatin readily induced effects that can be explained by an inhibited prenylation in Capan-2 cells [7], but not in the Panc-1 and the MIA PaCa-2 cell lines.…”

“…Thus, fluvastatin was shown to enhance the antiproliferatory effect of gemcitabine in MIA PaCa-2 pancreatic cancer cells [5]. Besides their in vitro effects, statins have been shown to inhibit pancreatic tumor growth in vivo [3,5,7]. In a recent study performed on nude mice it was shown that different statins decreased the tumor growth of transplanted Capan-2 cells [7].…”

“…Besides their in vitro effects, statins have been shown to inhibit pancreatic tumor growth in vivo [3,5,7]. In a recent study performed on nude mice it was shown that different statins decreased the tumor growth of transplanted Capan-2 cells [7]. This effect was explained by an inhibited cholesterol synthesis and an inhibited prenylation of signaling proteins such as Ras.…”

Rosuvastatin induces apoptosis in cultured human papillary thyroid cancer cells

“…Statins not only inhibit cholesterol synthesis but also prevent isoprenoid formation and decrease the membrane translocation and activation of the small GTPases and their downstream effectors by inhibiting mevalonate synthesis via blocking HMG-CoA reductase (Alegret & Silvestre 2006, Katsiki et al 2009). The effect of statins on cancer cells has been a subject of numerous studies (Zhong et al 2003, Campbell et al 2006, Gbelcová et al 2008. Statins show antineoplastic activity by inhibiting proliferation and activating apoptosis or autophagy in various cancer cell lines (Bifulco et al 1999, Sassano & Platanias 2008, Parikh et al 2010.…”

“…A number of studies demonstrated antineoplastic effects of statins (Campbell et al 2006, Sivaprasad et al 2006. The antiproliferative effects of statins were demonstrated in in vitro studies on hepatocellular carcinoma (Kawata et al 1994), lung (Hawk et al 1996), breast (Campbell et al 2006), and pancreatic cancer cells (Gbelcová et al 2008). These effects appear to be generated either via effects on cell cycle and induction of growth suppression or via induction of apoptosis of malignant cells (Sassano & Platanias 2008).…”