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.