Don't Judge a Book by Its Cover: The Role of Statins in Liver Cancer

Abstract

Statins, which are inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, are an effective pharmacological tool for lowering blood cholesterol levels. This property makes statins one of the most popular drugs used primarily to prevent cardiovascular diseases, where hyperlipidemia is a significant risk factor that increases mortality. Nevertheless, studies conducted mainly in the last decade have shown that statins might prevent and treat liver cancer, one of the leading causes of cancer-related mortality worldwide. This narrative review summarizes the scientific achievements to date regarding the role of statins in liver tumors. Molecular biology tools have revealed that cell growth and proliferation can be inhibited by statins, which further inhibit angiogenesis. Clinical studies, supported by meta-analysis, confirm that statins are highly effective in preventing and treating hepatocellular carcinoma and cholangiocarcinoma. However, this effect may depend on the statin's type and dose, and more clinical trials are required to evaluate clinical effects. Moreover, their potential hepatotoxicity is a significant caveat for using statins in clinical practice. Nevertheless, this group of drugs, initially developed to prevent cardiovascular diseases, is now a key candidate in hepato-oncology patient management. The description of new drug-statin-like structures, e.g., with low toxicity to liver cells, may bring another clinically significant improvement to current cancer therapies.

Keywords: 3-hydroxy-3-methylglutaryl-coenzyme A reductase; cholesterol; liver cancer; statins.

Figure 1

Chemical structures of FDA-approved statins. Different shades of red—different pharmacophores; different shades of blue—different ring structures; different shades of green—different side groups. The purple frame includes natural statins, the pink semi-synthetic, and the yellow synthetic. The gray text indicates hydrophilic statins.

Figure 2

The molecular processes underlying statin anti-cancer effects in liver cancer. The use of statins in mevalonate pathway modulation allows for the inhibition of tumorigenesis. Statins competitively bind to HMGCR, an enzyme responsible for the catalysis of HMG-CoA to mevalonate, consequently reducing the amount of farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Statins’ disruption of the mevalonate pathway impacts the prenylation of Ras and Rho proteins. These impede the potential development and progression of cancer cells. Statin-induced molecular changes lead to an increase in apoptosis and autophagy within cancer cells. Thus, inhibiting angiogenesis while also modulating the tumor microenvironment (TME) effectively impeding cancer cell growth. (Created with BioRender.com, accessed on 15 October 2023).