Abstract
Lung cancer is the most common cause of cancer-related death. Nonetheless, a decrease in overall incidence and mortality has been observed in the last 30 years due to prevention strategies and improvements in the use of chemotherapeutic agents. In recent studies, Simvastatin (SIM) has demonstrated anti-tumor activity, as well as potent chemopreventive action. As an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA), SIM has been shown to stimulate apoptotic cell death. In this study, an MTT assay revealed the cytotoxic activity of SIM against human large cell lung cancer (Non-small cell lung cancer; NSCLC) cells (NCI-H460); however, induced apoptosis was not observed in NCI-H460 cells. Protein expression levels of cell cycle regulating proteins Cdk4, Cyclin D1, p16 and p27 were markedly altered by SIM. Collectively, our results indicate that SIM inhibits cell proliferation and arrests NCI-H460 cell cycle progression via inhibition of cyclin-dependent kinases and cyclins and the enhancement of CDK inhibitors p16 and p27. Our findings suggest that, in addition to the known effects on hypercholesterolemia therapy, SIM may also provide antitumor activity in established NSCLC.
Highlights
Lung cancer is the leading cause of cancer-related death worldwide
SIM induced G1 cell cycle arrest in NCI-H460 cells, indicating the existence of an additional mechanism by which SIM may inhibit the proliferation of NSCLC cells
To analyze the biological mechanisms underlying SIM-induced G1 cell cycle arrest, we evaluated the protein and gene expressions of CDKs and cyclins, as well as CDK-inhibitors p16 and p27
Summary
Lung cancer is the leading cause of cancer-related death worldwide. The survival rate of lung carcinoma has remained relatively unchanged below 15% for the past two decades [1]. NSCLC accounts for approximately 80% of all forms of lung cancer, and early-stage NSCLC is potentially curative through complete surgical resection. The overall five-year survival rate for these patients is only 45% to 70%, due to metastatic recurrence [2]. Statins have been shown to alter several cellular mechanisms, resulting in apoptosis and reduced tumor cell growth, as well as angiogenesis and impaired metastatic processes [3]. Simvastatin (SIM), like statins, is used in hypercholesterolemia therapy to inhibit the 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase, which catalyzes the conversion of HMG-CoA to mevalonate [4]
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