Research Article
Dose-dependent effects of simvastatin, atorvastatin and rosuvastatin on apoptosis and inflammation pathways on cancerous lung cells
Abstract
The aim of study was to investigate the anti-proliferative and inflammatory effects of atorvastatin, rosuvastatin, and simvastatin in lung cancer. The effects of statins were investigated in Vero, BEAS-2B, and A549 cell lines. In addition to expressions of BAX, BCL-2, TNFα, IL-10, IL-6, protein levels of TNFα, IL-10, IL-6 were determined. Cell viability and MDA were also measured. While the cell numbers in groups with low doses of statins were found to be approximately 1x106/mL, proliferation was inhibited at higher rates containing high doses. Simvastatin, rosuvastatin, and high dose atorvastatin upregulated the BAX, while high dose of atorvastatin and both doses of rosuvastatin caused downregulation in BCL-2. All statin groups had higher MDA. Simvastatin and high dose rosuvastatin upregulated TNFα. While low dose simvastatin and atorvastatin and high dose atorvastatin and rosuvastatin upregulated IL-10, IL-6 was upregulated with a low dose of rosuvastatin. TNFα was higher in simvastatin and rosuvastatin groups. IL-10 was highest in rosuvastatin groups. Atorvastatin groups had lower IL-6. Although cell numbers have been reduced by all statins, rosuvastatin is more effective on studied genes.
Supporting Institution
This study was financially supported by the Scientific Research Projects Coordination of Hatay Mustafa Kemal University (Project number: 20.M.017).
Project Number
20.M.017
References
- Coogan PF, Smith J, Rosenberg L (2007): Statin use and risk of colorectal cancer. J Natl Cancer Inst, 99, 32–40.
- Crescencio ME, Rodríguez E, Páez A, et al (2009): Statins inhibit the proliferation and induce cell death of human papilloma virus positive and negative cervical cancer cells. Int J Biomed Sci, 5, 411.
- Du G, Song Y, Zhang T, et al (2014): Simvastatin attenuates TNF‑α‑induced apoptosis in endothelial progenitor cells via the upregulation of SIRT1. Int J Mol Med, 34, 177–182.
- Eckert GP, Müller WE, Wood GW (2007): Cholesterol-lowering drugs and Alzheimer’s disease. Future Lipidol, 2, 423–432.
- Esterbauer H, Cheeseman KH (1990): Determination of aldehydic lipid peroxidation products: malonaldehyde and 4-hydroxynonenal. Methods in Enzymology, 186, 407-421.
- Gauthaman K, Manasi N, Bongso A (2009): Statins inhibit the growth of variant human embryonic stem cells and cancer cells in vitro but not normal human embryonic stem cells. Br J Pharmacol, 157, 962–973.
- Hindler K, Cleeland CS, Rivera E, et al (2006): The role of statins in cancer therapy. Oncologist, 11, 306–315.
- Hruz T, Wyss M, Docquier M, et al (2011): RefGenes: identification of reliable and condition specific reference genes for RT-qPCR data normalization. BMC Genomics, 12, 1–14.
- Jemal A, Siegel R, Xu J, et al (2010): Cancer statistics. CA: Cancer J Clin, 60, 277–300.
- Kaneko R, Tsuji N, Asanuma K, et al (2007): Surviving down-regulation plays a crucial role in 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor-induced apoptosis in cancer. J Biol Chem, 282, 19273–19281.
- Karaliotas GI, Mavridis K, Scorilas A, et al (2015): Quantitative analysis of the mRNA expression levels of BCL2 and BAX genes in human osteoarthritis and normal articular cartilage: An investigation into their differential expression. Mol Med Rep, 12, 4514–4521.
- Keller C, Keller P, Marshal S, et al (2003): IL-6 gene Expr Hum adipose tissue response to Exerc Carbohydr ingestion. J Physiol, 550, 927–931.
- Kones R (2011): Primary prevention of coronary heart disease: integration of new data, evolving views, revised goals, and role of rosuvastatin in management. A comprehensive survey. Drug Des Devel Ther, 5, 325.
- Lee KJ, Moon JY, Choi HK, et al (2010): Immune regulatory effects of simvastatin on regulatory T cell‐mediated tumour immune tolerance. Clin Exp Immunol, 161, 298–305.
- Livak KJ, Schmittgen TD (2001): Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. Methods, 25, 402–408.
- Lowry OH, Rosebrough NJ, Farr AL, et al (1951): Protein measurement with the Folin phenol reagent. J Biol Chem, 193, 265–275.
- Minichsdorfer C, Wasinger C, Sieczkowski E, et al (2015): Tocilizumab unmasks a stage-dependent interleukin-6 component in statin-induced apoptosis of metastatic melanoma cells. Melanoma Res, 25, 284.
- Molina JR, Yang P, Cassivi SD, et al (2008): Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc, 83, 584-594.
- Mosmann T (1983): Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods, 65, 55-63.
- Motawi TK, Teleb ZA, El-Boghdady NA, et al (2014): Effect of simvastatin and naringenin coadministration on rat liver DNA fragmentation and cytochrome P450 activity: an in vivo and in vitro study. J Physiol Biochem, 70, 225–237.
- Olie RA, Hafner C, Küttel R, et al (2002): Bcl-2 and bcl-xL antisense oligonucleotides induce apoptosis in melanoma cells of different clinical stages. J Invest Dermatol, 118, 505–512.
- Pal S, Ghosh M, Ghosh S, et al (2015): Atorvastatin induced hepatic oxidative stress and apoptotic damage via MAPKs, mitochondria, calpain and caspase12 dependent pathways. Food Chem Toxicol, 83, 36–47.
- Perucha E, Melchiotti R, Bibby JA, et al (2019): The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells. Nat Commun, 10, 1–13.
- Raul R, Antonio TM, Laura ME, et al (2020): Statins: Could an Old Friend Help the Fight Against COVID-19? Br J Pharmacol, 177, 4873-4886.
- Reddy KB (2010): MicroRNA (miRNA) in cancer. Cancer Cell Int, 15, 1–6.
- Rio DC, Ares M, Hannon GJ, et al (2010): Purification of RNA using TRIzol (TRI reagent). Cold Spring Harb Protoc 6, 5439.
- Spampanato C, De Maria S, Sarnataro M, et al (2012): Simvastatin inhibits cancer cell growth by inducing apoptosis correlated to activation of Bax and down-regulation of BCL-2 gene expression. Int J Oncol, 40, 935–941.
- Stancu C, Sima A (2001): Statins: mechanism of action and effects. J Cell Mol Med, 5, 378–387.
- Vors C, Allaire J, Marin J, et al (2017): Inflammatory gene expression in whole blood cells after EPA vs. DHA supplementation: Results from the ComparED study. Atherosclerosis, 257, 116–122.
- Wong WWL, Dimitroulakos J, Minden MD, et al (2002): HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis. Leukemia, 16, 508–519.
- Wood WG, Igbavboa U, Muller WE, et al (2013): Statins, Bcl-2, and apoptosis: cell death or cell protection? Mol Neurobiol, 48, 308–314.
Year 2023,
, 141 - 148, 24.03.2023
Abstract
Project Number
20.M.017
References
- Coogan PF, Smith J, Rosenberg L (2007): Statin use and risk of colorectal cancer. J Natl Cancer Inst, 99, 32–40.
- Crescencio ME, Rodríguez E, Páez A, et al (2009): Statins inhibit the proliferation and induce cell death of human papilloma virus positive and negative cervical cancer cells. Int J Biomed Sci, 5, 411.
- Du G, Song Y, Zhang T, et al (2014): Simvastatin attenuates TNF‑α‑induced apoptosis in endothelial progenitor cells via the upregulation of SIRT1. Int J Mol Med, 34, 177–182.
- Eckert GP, Müller WE, Wood GW (2007): Cholesterol-lowering drugs and Alzheimer’s disease. Future Lipidol, 2, 423–432.
- Esterbauer H, Cheeseman KH (1990): Determination of aldehydic lipid peroxidation products: malonaldehyde and 4-hydroxynonenal. Methods in Enzymology, 186, 407-421.
- Gauthaman K, Manasi N, Bongso A (2009): Statins inhibit the growth of variant human embryonic stem cells and cancer cells in vitro but not normal human embryonic stem cells. Br J Pharmacol, 157, 962–973.
- Hindler K, Cleeland CS, Rivera E, et al (2006): The role of statins in cancer therapy. Oncologist, 11, 306–315.
- Hruz T, Wyss M, Docquier M, et al (2011): RefGenes: identification of reliable and condition specific reference genes for RT-qPCR data normalization. BMC Genomics, 12, 1–14.
- Jemal A, Siegel R, Xu J, et al (2010): Cancer statistics. CA: Cancer J Clin, 60, 277–300.
- Kaneko R, Tsuji N, Asanuma K, et al (2007): Surviving down-regulation plays a crucial role in 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor-induced apoptosis in cancer. J Biol Chem, 282, 19273–19281.
- Karaliotas GI, Mavridis K, Scorilas A, et al (2015): Quantitative analysis of the mRNA expression levels of BCL2 and BAX genes in human osteoarthritis and normal articular cartilage: An investigation into their differential expression. Mol Med Rep, 12, 4514–4521.
- Keller C, Keller P, Marshal S, et al (2003): IL-6 gene Expr Hum adipose tissue response to Exerc Carbohydr ingestion. J Physiol, 550, 927–931.
- Kones R (2011): Primary prevention of coronary heart disease: integration of new data, evolving views, revised goals, and role of rosuvastatin in management. A comprehensive survey. Drug Des Devel Ther, 5, 325.
- Lee KJ, Moon JY, Choi HK, et al (2010): Immune regulatory effects of simvastatin on regulatory T cell‐mediated tumour immune tolerance. Clin Exp Immunol, 161, 298–305.
- Livak KJ, Schmittgen TD (2001): Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. Methods, 25, 402–408.
- Lowry OH, Rosebrough NJ, Farr AL, et al (1951): Protein measurement with the Folin phenol reagent. J Biol Chem, 193, 265–275.
- Minichsdorfer C, Wasinger C, Sieczkowski E, et al (2015): Tocilizumab unmasks a stage-dependent interleukin-6 component in statin-induced apoptosis of metastatic melanoma cells. Melanoma Res, 25, 284.
- Molina JR, Yang P, Cassivi SD, et al (2008): Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc, 83, 584-594.
- Mosmann T (1983): Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods, 65, 55-63.
- Motawi TK, Teleb ZA, El-Boghdady NA, et al (2014): Effect of simvastatin and naringenin coadministration on rat liver DNA fragmentation and cytochrome P450 activity: an in vivo and in vitro study. J Physiol Biochem, 70, 225–237.
- Olie RA, Hafner C, Küttel R, et al (2002): Bcl-2 and bcl-xL antisense oligonucleotides induce apoptosis in melanoma cells of different clinical stages. J Invest Dermatol, 118, 505–512.
- Pal S, Ghosh M, Ghosh S, et al (2015): Atorvastatin induced hepatic oxidative stress and apoptotic damage via MAPKs, mitochondria, calpain and caspase12 dependent pathways. Food Chem Toxicol, 83, 36–47.
- Perucha E, Melchiotti R, Bibby JA, et al (2019): The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells. Nat Commun, 10, 1–13.
- Raul R, Antonio TM, Laura ME, et al (2020): Statins: Could an Old Friend Help the Fight Against COVID-19? Br J Pharmacol, 177, 4873-4886.
- Reddy KB (2010): MicroRNA (miRNA) in cancer. Cancer Cell Int, 15, 1–6.
- Rio DC, Ares M, Hannon GJ, et al (2010): Purification of RNA using TRIzol (TRI reagent). Cold Spring Harb Protoc 6, 5439.
- Spampanato C, De Maria S, Sarnataro M, et al (2012): Simvastatin inhibits cancer cell growth by inducing apoptosis correlated to activation of Bax and down-regulation of BCL-2 gene expression. Int J Oncol, 40, 935–941.
- Stancu C, Sima A (2001): Statins: mechanism of action and effects. J Cell Mol Med, 5, 378–387.
- Vors C, Allaire J, Marin J, et al (2017): Inflammatory gene expression in whole blood cells after EPA vs. DHA supplementation: Results from the ComparED study. Atherosclerosis, 257, 116–122.
- Wong WWL, Dimitroulakos J, Minden MD, et al (2002): HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis. Leukemia, 16, 508–519.
- Wood WG, Igbavboa U, Muller WE, et al (2013): Statins, Bcl-2, and apoptosis: cell death or cell protection? Mol Neurobiol, 48, 308–314.
There are 31 citations in total.
Details
| Primary Language | English |
|---|---|
| Subjects | Veterinary Surgery |
| Journal Section | Research Article |
| Authors | |
| Project Number | 20.M.017 |
| Publication Date | March 24, 2023 |
| Published in Issue | Year 2023 |