Differential effects of hydrophilic pravastatin and hydrophobic/lipophilic simvastatin on the growth of tumor cells from different organ sites.

B111

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 but little is known about their effects on cancer. Mechanistically, targeting HMGCR pathway primarily influences cholesterol biosynthesis and prenylation of signaling proteins. Pravastatin is a hydrophilic statin that is selectively taken up by sodium-independent organic anion transporter peptide-1B1 (OATP1B1) exclusively expressed in liver. Simvastatin is a hydrophobic/lipophilic statin that generally enters cells by other mechanisms. Poorly differentiated and well-differentiated cancer cell lines were selected from a variety of tissue origins and examined for their response to pravastatin and simvastatin. Simvastatin dose dependently inhibited the growth of most tumor cell lines more effectively than pravastatin. The liver specific OATP1B1 transporter facilitated responsiveness to pravastatin and was only found in the normal liver and primary hepatocytes. Primary hepatocytes were the only cells to respond significantly to hydrophilic pravastatin. Poorly-differentiated cancer cells were generally more responsive to hydrophobic/lipophilic simvastatin than well-differentiated cancer cells. The inhibition of growth was accompanied by dramatic changes in cellular morphology and distinct alterations in their mitochondrial networks in the most responsive lines. These findings should be taken into account when evaluating meta-data that neglect to take into account chemical and mechanistic properties of statins.