BACKGROUND: Fibrates are widely used hypolipidemic drugs, which serve as ligand of peroxisome proliferator-activated receptor α (PPARα). Recently, they have also been considered as potential anticancer agents. We studied effect of fibrates treatment on cell proliferation, expression of CYP2J2 and concomitant changes in expression of cell cycle regulatory proteins in three different human cell lines: HEK293, HepG2, and HT-29. METHODS: We used WST-1 viability test, western blot and immunocytochemistry for detection of proteins of interests and analysis of cell cycle. RESULTS: Our results showed that at lower concentrations of all tested fibrates, viability of all tested cell lines is increased, whereas at higher concentrations, repression is apparent. Unfortunately, the viability of tested cells is predominantly increased in a range of concentration which is reached in patient plasma. This phenomenon is accompanyed by elevation of CYP2J2, increased number of cyclin E-positive cells and decreased number of Cdc25A-positive cells in all tested cell lines, and elevated cyclin A expression in HepG2 and HT-29. These changes are concentration-dependent. We suppose that increased level of CYP2J2 could explain enhanced cell proliferation in lower concentration of fibrates. CONCLUSION: Based on our results, we suggested there is no anti-cancer effect of fibrates in tested carcinoma cell lines.

Department of Clinical and Molecular Pathology and Laboratory of Molecular Pathology Faculty of Medicine and Dentistry Palacky University Hnevotinska 3 775 15 Olomouc Czech Republic

Department of Histology and Embryology Faculty of Medicine and Dentistry Palacky University Olomouc Hnevotinska 3 775 15 Olomouc Czech Republic

Institute of Molecular and Translation Medicine Faculty of Medicine and Dentistry Palacky University Hnevotinska 5 775 15 Olomouc Czech Republic

Zobrazit více v PubMed

Peters JM, Shah YM, Gonzales FJ. The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention. Nat Rew Cancer. 2012;12:181–195. PubMed PMC

Burns KA, Vanden Heuvel JP. Modulation of PPAR activity via phosphorylation. Biochim Biophys Acta. 2007;1771:952–960. doi: 10.1016/j.bbalip.2007.04.018. PubMed DOI PMC

Pyper SR, Viswakarma N, Yu S, Reddy JK. PPARα: energy combustion, hypolipidemia, inflammation and cancer. Nucl Recept Signal. 2010;8:e002. doi: 10.1621/nrs.08002. PubMed DOI PMC

Rakhshandehroo M, Knoch B, Müller M, Kersten S. Peroxisome proliferator-activated receptor alpha target genes. PPAR Res. 2010;2010:612089. doi: 10.1155/2010/612089. PubMed DOI PMC

Urbanska K, Pannizzo P, Grabacka M, Croul S, Del Valle L, Khalili K, Reiss K. Activation of PPARα inhibits IGF-I-mediated growth and survival responses in medulloblastoma cell lines. Int J Cancer. 2008;123:1015–1024. doi: 10.1002/ijc.23588. PubMed DOI PMC

Panigrahy D, Kaipainen A, Huang S, Butterfield CE, Barnés CM, Fannon M, Laforme AM, Chaponis DM, Folkman J, Kieran MW. PPARα agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibitor. Proc Natl Acad Sci U S A. 2008;105:985–990. doi: 10.1073/pnas.0711281105. PubMed DOI PMC

Jiao HL, Zhao BL. Cytotoxic effect of peroxisome proliferator fenofibrate on human HepG2 hepatoma cell line and relevant mechanisms. Toxicol Appl Pharmacol. 2002;185:172–179. doi: 10.1006/taap.2002.9538. PubMed DOI

Liang H, Kowalczyk P, Junco JJ, Klug-De Santiago HL, Malik G, Wei SJ, Slaga TJ. Differential effects on lung cancer proliferation by agonists of glucocorticoid and PPARα receptors. Mol Carcinog. 2014;53:753–763. doi: 10.1002/mc.22029. PubMed DOI

Saidi SA, Holland CM, Charnock-Jones DS, Smith SK. In vitro and in vivo effects of the PPAR-alpha agonists fenofibrate and retinoic acid in endometrial cancer. Mol Cancer. 2006;5:13. doi: 10.1186/1476-4598-5-13. PubMed DOI PMC

Grabacka M, Plonka PM, Urbanska K, Reiss K. Peroxisome proliferator-activated receptor α activation decreases metastatic potential of melanoma cells in vitro via down-regulation of Akt. Clin Cancer Res. 2006;12:3028–3036. doi: 10.1158/1078-0432.CCR-05-2556. PubMed DOI

Strakova N, Ehrmann J, Bartos J, Malikova J, Dolezel J, Kolar Z. Peroxisome proliferator-activated receptor (PPAR) agonists affect cell viability, apoptosis and expression of cell cycle related proteins in cell lines of glial brain tumors. Neoplasma. 2005;52:126–136. PubMed

Suchanek KM, May FJ, Robinson JA, Lee WJ, Holman NA, Monteith GR, Roberts-Thomson SJ. Peroxisome proliferator-activated receptor α in the human breast cancer cell line MCF-7 and MDA-MB-231. Mol Carcinog. 2002;34:165–171. doi: 10.1002/mc.10061. PubMed DOI

Grabacka M, Reiss K. Anticancer properties of PAPRα-effects on cellular metabolism and inflammation. PPAR Res. 2008;2008:930705. doi: 10.1155/2008/930705. PubMed DOI PMC

Vamecq J, Colet JM, Vanden Eynde JJ, Briand G, Porcher N, Rocchi S. PPARs: Interference with Warburg’s effect and clinical anticancer trials. PPAR Res. 2012;2012:304760. doi: 10.1155/2012/304760. PubMed DOI PMC

Kersten S, Mandard S, Escher P, Gonzalez FJ, Tafuri S, Desvergne B, Wahli W. The peroxisome proliferator-activated receptor α regulates amino acid metabolism. FASEB J. 2001;15:1971–1978. doi: 10.1096/fj.01-0147com. PubMed DOI

Shen GF, Jiang JG, Fu XN, Wang DW. Promotive effects of epoxyeicosatrienoic acids (EETs) on the proliferation of tumor cells. Ai Zheng. 2008;27:390–395. PubMed

Pozzi A, Propescu V, Yang S, Mei S, Shi M, Puolitaival SM, Caprioli RM, Capdevila JH. The anti-tumorogenic properties of peroxisomal proliferator-activated receptor α are arachidonic acid epoxygenase-mediated. J Biol Chem. 2010;285:12840–12850. doi: 10.1074/jbc.M109.081554. PubMed DOI PMC

Jiang JG, Chen CL, Card JW, Yang S, Chen JX, Fu XN, Ning YG, Xiao X, Zeldin DC, Wang DW. Cytochrome P450 2 J2 promotes the neoplastic phenotype of carcinoma cells and is up-regulated in human tumors. Cancer Res. 2005;65(11):4707–4715. doi: 10.1158/0008-5472.CAN-04-4173. PubMed DOI

Jiang JG, Ning YG, Chen C, Ma D, Liu ZJ, Yang S, Zhou J, Xiao X, Zhang XA, Edin ML, Card JW, Wang J, Zeldin DC, Wang DW. Cytochrome P450 epoxygenase promotes human cancer metastasis. Cancer Res. 2007;67(14):6665–6674. doi: 10.1158/0008-5472.CAN-06-3643. PubMed DOI

Wei X, Zhang D, Dou X, Niu N, Huang W, Bai J, Zhang G. Elevated 14,15-epoxyeicosatrienoic acid by increasing of cytochrome P450 2C8, 2C9 and 2 J2 and decreasing of soluble epoxide hydrolase associated with aggressiveness of human breast cancer. BMC Cancer. 2014;14:841. doi: 10.1186/1471-2407-14-841. PubMed DOI PMC

Vu-Dac N, Schoonjans K, Kosykh V, Dallongeville J, Fruchart JC, Staels B, Auwerx J. Fibrates increase human apolipoprotein A-II expression through activation of the peroxisome proliferator-activated receptor. J Clin Invest. 1995;96:741–750. doi: 10.1172/JCI118118. PubMed DOI PMC

Cheema SK, Agellon LB. The murine and human cholesterol 7alpha-hydroxylase gene promoters are differentially responsive to regulation by fatty acids mediated via peroxisome proliferator-activated receptor alpha. J Biol Chem. 2000;275:12530–12536. doi: 10.1074/jbc.275.17.12530. PubMed DOI

Chinetti G, Griglio S, Antonucci M, Torra IP, Delerive P, Majd Z, Fruchart JC, Chapman J, Najib J, Staels B. Activation of proliferation-activated receptor alpha and gamma induces apoptosis of human monocyte-derived macrophages. J Biol Chem. 1998;273:25573–25580. doi: 10.1074/jbc.273.40.25573. PubMed DOI

Bordji K, Grillasca JP, Gouze JN, Magdalou J, Schohn H, Keller JM, Bianchi A, Dauca M, Netter P, Terlain B. Evidence for the presence of peroxisome-proliferator-activated receptor (PPAR) alpha nad gamma and retinoid Z receptor in cartilage. PPAR gamma activation modulates the effects of interleukin-1 on rat chondrocytes. J Biol Chem. 2000;275:12243–12250. doi: 10.1074/jbc.275.16.12243. PubMed DOI

Reynders V, Loitsch S, Steinhauer C, Wagner T, Steinhilber D, Bargon J. Peroxisome proliferator-activated receptor alpha (PPAR alpha) down-regulation in cystic fibrosis lymphocytes. Respir Res. 2006;7:104–118. doi: 10.1186/1465-9921-7-104. PubMed DOI PMC

Umemoto T, Fujiki Y. Ligand-dependent nucleo-cytoplasmic shuttling of peroxisome proliferator-activated receptors, PPARα and PPARγ. Genes Cells. 2012;17:579–596. doi: 10.1111/j.1365-2443.2012.01607.x. PubMed DOI

Rother K, Kirschner R, Sänger K, Böhlig L, Mössner J, Engeland K. p53 downregulation expression of the G1/S cell cycle phosphatase Cdc25A. Oncogene. 2007;26:1949–1953. doi: 10.1038/sj.onc.1209989. PubMed DOI

When Activator and Inhibitor of PPARα Do the Same: Consequence for Differentiation of Human Intestinal Cells