Differential Effects of Pravastatin and Simvastatin on the Growth of Tumor Cells from Different Organ Sites

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.

Synergistic Cytotoxic Effect of Statins and Bisphosphonates on Squamous Cell Carcinoma Cell Line

“…Aln is a farnesyl pyrophosphate synthase inhibitor and Sv is an HMG CoA reductase inhibitor. The combination of both drugs can effectively inhibit the mevalonate cascade and the generation of downstream isoprenoids and geranylgeranylation of proteins [23].…”

“…There is increasing evidence that BPs also directly inhibit cancer cells by acting either on tumour cell proliferation/survival or by having an anti-angiogenic potential [22]. Many in vitro studies have established the antiproliferative effects of pamidronate or Aln on different cancer cells, such as osteosarcoma, breast, myeloma, and melanoma and recently on neuroblastoma cancer cells [23].…”

Statins and pancreatic cancer

“…The existence of differential effects between hydrophobic statins such as simvastatin and hydrophilic statins such as pravastatin have been proposed, as simvastatin appears to produce greater antitumor effects compared with pravastatin in several cancer cell lines (excluding pancreatic) in vitro (69). However, another study demonstrated that, although simvastatin produced the greatest antitumor effects in vitro, rosuvastatin, cerivastatin and fluvastatin had the most potent antitumor effects in animal models of PDAC at the recommended human doses, with all statins (hydrophobic and hydrophilic) except pravastatin exerting inhibitory effects on intracellular Ras translocation (70).…”

The role of statins as therapeutic agents in cancer

“…Poorly-differentiated cancer cells were generally more responsive to simvastatin than well-differentiated cancer cells, and the levels of HMG-CoA reductase expression did not consistently correlate with response to statin treatment. Hydrophilic drug pravastatin was ineffective in inhibiting the growth or altering the biologic behavior of selected tumor cell lines (Menter et al 2011).…”

“…In contrast, lipophilic statins enter the liver by passive diffusion (Alfaqih et al 2017). The sodium-independent organic anion transporter protein-1B1 (OATP1B1) is exclusively expressed in liver (Menter et al 2011). However, studies on tissue samples revealed decreased levels of OATP1B1 in hepatocellular carcinoma tumor samples compared to normal liver (Cui et al 2003;Zollner et al 2005).…”