Abstract
3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) inhibitors, commonly known as statins, may possess cancer preventive and therapeutic properties. Statins are effective suppressors of cholesterol synthesis with a well-established risk-benefit ratio in cardiovascular disease prevention. Mechanistically, targeting HMGCR activity primarily influences cholesterol biosynthesis and prenylation of signaling proteins. Pravastatin is a hydrophilic statin that is selectively taken up by a sodium-independent organic anion transporter protein-1B1 (OATP1B1) exclusively expressed in liver. Simvastatin is a hydrophobic statin that enters cells by other mechanisms. Poorly-differentiated and well-differentiated cancer cell lines were selected from various tissues and examined for their response to these two statins. Simvastatin inhibited the growth of most tumor cell lines more effectively than pravastatin in a dose dependent manner. Poorly-differentiated cancer cells were generally more responsive to simvastatin than well-differentiated cancer cells, and the levels of HMGCR expression did not consistently correlate with response to statin treatment. Pravastatin had a significant effect on normal hepatocytes due to facilitated uptake and a lesser effect on prostate PC3 and colon Caco-2 cancer cells since the OATP1B1 mRNA and protein were only found in the normal liver and hepatocytes. The inhibition of cell growth was accompanied by distinct alterations in mitochondrial networks and dramatic changes in cellular morphology related to cofilin regulation and loss of p-caveolin. Both statins, hydrophilic pravastatin and hypdrophobic simvastatin caused redistribution of OATP1B1 and HMGCR to perinuclear sites. In conclusion, the specific chemical properties of different classes of statins dictate mechanistic properties which may be relevant when evaluating biological responses to statins.
Highlights
Statins may be useful for the prevention and treatment of cancer [1,2,3,4]
In this study we present the comparative effects of pravastatin or simvastatin on normal hepatocytes as well as in tumor cells isolated from a variety of organ sites
Based on MTT assays, simvastatin effects were more pronounced than pravastatin on the growth of all the tumor cell lines examined except for squamous cancer cell line SCCM7 and pancreatic cancer cell line Capan-1(Figure 1)
Summary
Statins were first isolated as fungal metabolites that exhibited potent cholesterol lowering activity through the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) [5]. These compounds were soon recognized to lower cholesterol through two systemic mechanisms. Statins reversibly inhibit HMGCR and reduce intracellular pools of cholesterol. This results in an increase in low-density lipoprotein (LDL)-receptors on cell surfaces leading to clearance and catabolism of LDL [6]. Some reports indicate that hypocholesterolemia occurs in cancer due to increased use of cholesterol by tumors [10] whereas other reports have associated lower tissue cholesterol with malignancy [11]
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