Potential for Statins in the Chemoprevention and Management of Hepatocellular Carcinoma

Amedeo Lonardo; Paola Loria

J Gastroenterol Hepatol. 2012;27(11):1654-1664.

Abstract and Introduction

Abstract

Hepatocellular carcinoma (HCC) is a common, treatment-resistant malignancy with a complex molecular pathogenesis. Statins are a widely used class of cholesterol-lowering drugs with potential anticancer activity.
We reviewed the evidence for a role of statins in primary and secondary chemoprevention of HCC and slowing the course of otherwise incurable primary or recurrent disease. A literature search (key words: Statins, hepatocellular carcinoma) conducted to this end, retrieved 119 references. Here we summarize the history, mechanism of action and cardiovascular use of statins and highlight that statins can affect several pathways implicated in the development of HCC. In vitro and animal studies provide strong evidence for a favorable effect of statins on HCC. However, evidence in humans is conflicting. We discuss in full detail the methodological strengths and pitfalls of published data including three cohort studies suggesting that the use of statins may protect from the development of HCC and of a single trial reporting increased survival in those with advanced HCC randomized to receive statins. A remarkably hepato-safe class of drugs acting on both hepatocyte and endothelial cells, statins also have potentially beneficial effects in lowering portal hypertension. In conclusion, there is strong experimental evidence that statins are beneficial in chemopreventing and slowing the growth of HCC. However, randomized controlled trials are necessary in order to investigate the role of statins in the chemoprevention of HCC and in slowing the course of otherwise incurable disease in humans.

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Table 1. Anticancer effect of statins. Evidence from experimental studies
Author (ref)	Experimental model	Finding
Paragh⁴⁵	HCC cells were implanted under the left renal capsule of FLF1 hybrid rats. Fluvastatin was administered per os in 0.5, 2 and 20 mg/kg per day doses.	Fluvastatin administered pre- and post-tumor implantation showed a more intensive anticancer effect than treatment given post-tumor implantation alone.
Paragh⁴⁶	Rats pre-treated with 2 and 20 mg/kg per day fluvastatin, after 6 weeks were inoculated HCC cells under the left renal capsule.	Lovastatin had a dose-dependent inhibitory effect on primary and metastatic tumors. The inhibitory effect on growth and pyruvate kinase activity were higher and occurred earlier in metastases than in primary tumors.
Sutter⁴⁷	Statin induced apoptosis was characterized by a breakdown of the mitochondrial membrane potential, caspase activation and nuclear degradation. Furthermore, synergistic growth inhibition was obtained by the combination of statins with the PBR ligand FGIN-1–27. PBR ligands induced a downregulation of HMG-CoAR expression which may account for the enhanced sensitivity of HCC cells to statins.	Various statins inhibited the proliferation of HCC cells by inducing apoptosis and G1/S cell cycle arrest.
Kim⁴⁸	In vitro studies: Huh-7 cells (a well differentiated human HCC cell line) were used. In vivo studies: MH134 cells (a mouse HCC cell line) and 4-week old male C3H/He mice were used	Co-treatment with lovastatin and enzastaurin, a PKC inhibitor, synergistically suppressed HCC cell growth in vitro and in vivo.
Björkhem-Bergman.⁴⁹	These authors hypothesized that statins inhibit carcinogenesis via inhibition of ubiquinone synthesis in a rat model for liver cancer.	Lovastatin inhibits carcinogenesis despite unaffected cholesterol levels, at least in part, via inhibition of ubiquinone synthesis.
Yang⁵⁰	This study was conducted in various cell lines including human HCC cell lines Hep3B, HepG2, and Huh7; HCT116 wt and p53−/− cells. Murine embryonic fibroblast (MEF) cells. MEF autophagy-related gene 5−/− (Atg5−/−) cells.	Activation of AMPK by atorvastatin enhances p21 expression and ER stress response, leading to autophagy, which promotes the survival of cancer cells.
Gao⁵¹	The in vivo growth inhibitory effects of celecoxib, a cyclo-oxygenase-2 inhibitor, and fluvastatin was investigated in athymic nude mice implanted with HCC cell line BEL-7402 cells	The combination of celecoxib and fluvastatin enhanced inhibition of tumor growth, induction of apoptosis, inhibition of tumor cell proliferation, and inhibition of tumor angiogenesis compared with either treatment alone. The combination of celecoxib and fluvastatin also increased levels of the cyclin-dependent kinase inhibitor p21 (Waf1/Cip1), decreased levels of p-Akt, myeloid cell leukaemia-1 (Mcl-1) and survivin protein, but had no effect on Akt protein levels in tumors.
Cao²²	Transgenic model of MYC-induced HCC and human HCC-derived cell lines.	Iinhibition of HMG-CoA reductase suppresses MYC phosphorylation through Rac GTPase.
Shimizu⁵²	This study evaluated the effects of pitavastatin on the development of diethylnitrosamine (DEN)-induced liver preneoplastic lesions in C57BL/KsJ-db/db (db/db) obese mice.	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.
Tijeras-Raballand⁵³	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.	Rosuvastatin reduced the vessel anomalies and tumor growth and prolonged survival in HCC concurrent with activation of hepatic AMPK, decreased steatosis, free fatty acids, and aminotransferases levels, and the expression of TNF-α and interleukin-6 mRNAs in the liver; increased serum adiponectin levels suggesting attenuation of the chronic inflammation induced by steatosis.
Polo⁵⁴	This study conducted on human hepatocarcinoma cell line (Hep G2) determined the action of geraniol, in combination with simvastatin, and the effect of simvastatin, geraniol and the combination of both on the biosynthesis of lipids from [14C]-acetate.	The combination of simvastatin and geraniol synergistically inhibited cholesterol biosynthesis and proliferation of Hep G2 cell line.

AMPK, adenosine mono-phosphate kinase; ER, endoplasmic reticulum; HCC, hepatocellular carcinoma; PBR, peripheral benzodiazepine receptor; PKC, protein kinase C; TNF, tumor necrosis factor.

Table 2. Beneficial effects of statins in either preventing or curing hepatocellular carcinoma (HCC). Evidence from human studies
Author (Ref)	Method	Finding
Kawata⁵⁹	After withdrawal of eight out of 91 cases with advanced disease, 83 adults with unresectable HCC were enrolled in a RCT. Standard treatment with/without the potent HMG-CoA reductase inhibitor pravastatin, was compared with death as the primary endpoint. All patients underwent TAE followed by oral 5-FU 200 mg/day for 2 months. Patients were then randomly assigned to control (n = 42) and pravastatin 40 mg daily (n = 41) groups for 16.5 ± 9.8 months. Compliance with treatment was assessed by detecting pravastatin in urine.	Pravastatin was discontinued in all patients because of advancing disease and not because of any adverse effects of the medicine. Patients in the pravastatin group survived significantly longer than those in the control group (Median survival 18 months vs 9 months in controls p = 0.006). Analysis using the Cox proportional-hazards model showed that treatment with pravastatin was the significant factor contributing to prolonged survival (P = 0.02 for univariate analysis and P = 0.005 for multivariate analysis). This study suggests that pravastatin offers a survival advantage in the treatment of advanced HCC.
Friis⁶⁰	This population-based cohort study was conducted in Denmark taking advantage of the Central Population Register, offering valid linkage between cancer and prescription histories for each individual. Within the population of North Jutland county, which has nearly 500 000 inhabitants, 334 754 county residents who were 30–80 years of age during the period 1 January 1989 to 31 December 2002 were identified.	The age- and gender-standardized incidence rate of cancer overall was 596 per 100 000 person-years among statin users and 645 per 100 000 person-years among non-users, yielding an age- and gender-standardized incidence RR of 0.92 (95% CI, 0.83–1.02). No statistically significant decreased or increased risks were observed for any of the selected site-specific cancers including liver cancer.
El-Serag⁶¹	This matched case-control nested study was conducted within a cohort of patients with diabetes. Cases comprised incident HCC at least 6 months after entry in the cohort. Controls were identified by incidence density sampling from age and gender matched patients.	1303 cases and 5212 controls were examined. The mean age was 72 years and 99% were men. Only 34.3 % of cases had at least one filled prescription for statins vs. 53.1% of controls (adjusted OR for any statin prescription 0.74; 95% CI 0.64–0.87). In contrast, there were no significant associations between HCC and nonstatin lipid-lowering agents indicating that statins alone were associated with reduced HCC incidence. In order to reduce the potential confounding effect of existing liver disease, analyses were repeated in a subgroup of liver disease-free patients. Such analysis confirmed highly significant ORs for any statin prescription (0.63; 95% CI, 0.50–0.78). This study provides strong evidence that the use of statins is associated with a significant reduction in the risk of HCC in diabetics.
Chiu⁶²	This is a retrospective population-based case-control study conducted in Taiwan using the local National Health Insurance Research Database. Cases consisted of all ≥ 50 year old patients who had a first-time diagnosis of liver cancer between 2005 and 2008. Age and gender paired controls were matched to cases by index date. Adjusted ORs and 95% CIs (95% CI) were calculated through multiple logistic regression analysis.	1166 liver cancer cases and 1166 controls were examined. Using those individuals not taking statins as the reference group, those who had been prescribed statins below 215.4 defined daily dose (DDD) had ORs 0.62 (95% CI = 0.42–0.91) and those with cumulative statin use of 215.4 DDDs or more had ORs 0.63 (95% CI = 0.37–1.06). This study extends the finding that the use of statins may be associated with a reduced risk of liver cancer to a geographic area where viral hepatitis rather than metabolic disease represents the milieu in which this cancer usually develops.
Tsan⁶³	This is cohort study was conducted in the general Taiwan population using the local National Health Insurance Research Database as in the previous study by Chiu.⁶² The study cohort consisted of 33 413 patients with HBV infection. During the follow-up period, 1021 cases of HCC were observed.	Compared to no statin use, defined as < 28 cDDDs, the adjusted HRs for statins users were reduced as follows: 0.66 (95% CI = 0.44–0.99); 0.41 (95% CI = 0.27–0.61), and 0.34 (95% CI = 0.18–0.67) for 28–91; 91–365; and > 365 cDDDs, respectively. The risk of HCC in those with HBV infection was reduced by the use of statins in a dose-response manner in this survey from Taiwan.

cDDDs, cumulative defined daily doses; CI, confidence interval; DDD, defined daily dose; HBV, hepatitis B virus; OR, odds ratio; RCT, randomized clinical trial; RR, rate ratio; TAE, transcatheter arterial embolization.