Skip to main content

Advertisement

Log in

Inhibition of melanoma metastases by fenofibrate

  • Original Paper
  • Published:
Archives of Dermatological Research Aims and scope Submit manuscript

Abstract

The effect of fenofibrate, a ligand of peroxisome proliferator-activated receptor (PPAR) α, on the growth and metastatic potential of Bomirski hamster melanoma s.c. tumors, pigmented line (BHM Ma) was investigated in vivo. RT-PCR and Western-blot analyses revealed the presence of mRNA and protein of PPAR α in BHM Ma cells. The animals treated orally with fenofibrate developed significantly fewer metastatic foci in the lungs, as compared to the control group; however, primary tumor growth remained unaltered. This observation is interesting in respect of the potential use of fenofibrate in melanoma chemoprevention.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1A, B
Fig. 2A, B

Similar content being viewed by others

References

  1. Aranega A, Gonzalez FJ, Aranega AE, Muros MA, Fernandez JE, Velez C, Prados J, Alvarez L (1991) Effects of fibric acid derivatives on accumulation of actin in myocardiocytes. Int J Cardiol 33:47–54

    Article  PubMed  CAS  Google Scholar 

  2. Aranega AE, Velez MC, Gonzalez FJ, Melguizo C, Prados JC, Aranega A (1995) Modulation of cardiac intermediate filament proteins in the chick heart by fibric acid derivatives. Eur J Morphol 33:421–431

    PubMed  CAS  Google Scholar 

  3. Blane GF (1989) Review of European clinical experience with fenofibrate. Cardiology 76 [Suppl 1]:1–10

  4. Bomirski A, Slominski A, Bigda J (1988) The natural history of a family of transplantable melanomas in hamsters. Cancer Metastasis Rev 7:95–118

    PubMed  CAS  Google Scholar 

  5. Cardones AR, Murakami, T, Hwang ST (2003) CXCR4 enhances adhesion of B16 tumor cells to endothelial cells in vitro and in vivo via beta (1) integrin. Cancer Res 63:6751–6757

    PubMed  CAS  ISI  Google Scholar 

  6. Chinetti G, Fruchart JC, Staels B (2001) Peroxisome proliferator-activated receptors (PPARs): nuclear receptors with functions in the vascular wall. Z Kardiol 90 [Suppl 3]:125–132

  7. Chomczynski P, Sacchi N (1987) Single step method of RNA isolation by acid guanidinium thiocyanate–phenol–chloroform extraction. Anal Biochem 162:156–159

    Article  PubMed  CAS  Google Scholar 

  8. Dellavalle RP, Nicholas MK, Schilling LM (2003) Melanoma chemoprevention: a role for statins and fibrates? Am J Ther 10:203–210

    PubMed  Google Scholar 

  9. Demierre MF, Nathanson (2003) Chemoprevention of melanoma: an unexplored strategy. J Clin Oncol 21:158–165

    Article  PubMed  Google Scholar 

  10. Downs JR, Clearfield M, Weiss S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr (1998) Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 279:1615–1622

    Article  PubMed  CAS  ISI  Google Scholar 

  11. Elstner E, Muller C, Koshizuka K, Williamson E, Park D, Asou H, Shintaku P, Said JW., Heber D, Koeffler HP (1998) Ligands for peroxisome proliferator-activated receptor α and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice. Proc Natl Acad Sci U S A 95:8806–8811

    Article  PubMed  CAS  Google Scholar 

  12. Engebraaten O, Bjerkvig R, Berens ME (1991) Effects of alkyl-lysophospholipid on glioblastoma cell invasion into fetal rat brain tissue in vitro. Cancer Res 51:1713–1719

    PubMed  CAS  ISI  Google Scholar 

  13. Escher P, Wahli W (2000) Peroxisome proliferator-activated receptors: insight into multiple cellular functions. Mutat Res 448:121–138

    PubMed  CAS  Google Scholar 

  14. Farina HG, Bublik DR, Alonso DF, Gomez DE (2002) Lovastatin alters cytoskeleton organization and inhibits experimental metastasis of mammary carcinoma cells. Clin Exp Metastasis 19:551–559

    Article  PubMed  CAS  Google Scholar 

  15. Frishman WH, Rapier RC (1989) Lovastatin: an HMG-CoA reductase inhibitor for lowering cholesterol. Med Clin North Am 73:437–448

    PubMed  CAS  Google Scholar 

  16. Gonzalez F, Peters JM, Cattley RC (1990) Review: mechanism of action of the nongenotoxic peroxisome proliferators: role of the peroxisome proliferator-activated receptor α. J Natl Cancer Inst 90:1702–1709

    Google Scholar 

  17. Guan RJ, Ford JL, Fu YN, Li YZ, Shaw LM, Pardee AB (2000) Drg-1 as a differentiation-related, putative metastatic suppressor gene in human colon cancer. Cancer Res 60:749–755

    PubMed  CAS  Google Scholar 

  18. Hyrc K, Kapiszewska M, Cieszka K (1985) Differences in the electrophoretic mobilities of pigmented and non-pigmented melanoma cells. In: Schutt W, Klinkmann H (eds) Cell electrophoresis. Walter de Gruyter, Berlin New York, pp 451–457

  19. Jakobisiak M, Golab J (2003) Potential antitumor effects of statins (review). Int J Oncol 23:1055–1069

    PubMed  CAS  Google Scholar 

  20. Jani JP, Specht S, Stemmler N, Blanock K, Singh SV, Gupta V, Katoh A (1993) Metastasis of B16 F10 mouse melanoma inhibited by lovastatin, an inhibitor of cholesterol biosynthesis. Invasion Metastasis 13:314–324

    PubMed  CAS  Google Scholar 

  21. Keelan JA, Sato T A, Marvin KW, Lander J, Gilmour RS, Mitchell M. (1999) 15-Deoxy-Δ12,14-prostaglandin J2, a ligand for peroxisome proliferator-activated receptor-γ, induces apoptosis in JEG3 choriocarcinoma cells. Biochem Biophys Res Commun 262:579–585

    Article  PubMed  CAS  Google Scholar 

  22. Kier AB, Parker MT, Schroeder F (1988) Local and metastatic tumor growth and membrane properties of LM fibroblasts in athymic (nude) mice. Biochim Biophys Acta 938:434–446

    PubMed  CAS  Google Scholar 

  23. Kliewer SA, Umesono K, Noonan DJ, Heyman RA, Evans DM (1992) Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature 358:771–774

    Article  PubMed  CAS  ISI  Google Scholar 

  24. Kort WJ, Hulsmann WC, Stehman TE (1989) Modulation of metastatic ability by inhibition of cholesterol synthesis. Clin Exp Metastasis 7:517–523

    PubMed  CAS  Google Scholar 

  25. Kroetz D, Yook P, Costet P, Pineau T (1998) Peroxisome proliferator-activated receptor α (PPAR α) controls the hepatic CYP4A induction adaptive response to starvation and diabetes. J Biol Chem 273:31581–31589

    Article  PubMed  CAS  Google Scholar 

  26. Laemmli UK (1970) Cleavage of structural proteins during assembly of the head of bacteriophage T4. Nature 227:680–685

    Article  PubMed  CAS  ISI  Google Scholar 

  27. Lens MB, Dawes M (2004) Global perspectives of contemporary epidemiological trends of cutaneous malignant melanoma. Br J Dermatol 150:179–185

    Article  PubMed  CAS  Google Scholar 

  28. Luisi BF, Xu WX, Otwinowski Z, Freedman LP, Yamamoto KR, Sigler PB (1991) Crystallographic analysis of interaction of the glucocorticoid receptor with DNA. Nature 352:497–505

    Article  PubMed  CAS  ISI  Google Scholar 

  29. Lukiewicz S, Pilas B, Nowicka J, Cieszka K, Gurbiel R (1981) Molecular and cellular basis of different radiosensitivity in pigmented and nonpigmented hamster melanoma cells. In: Seiji H (ed) Pigment cell. Phenotypic expression in pigment cells. Proceedings of the XIth International Pigment Cell Conference, Sendai, Japan. University of Tokyo Press, Tokyo, pp 23–29

  30. Martin G, Duez H, Blanquart C, BerezowskiV, Poulain P, Fruchart JC, Najib-Fruchart J, Glineur C, Staels B (2001) Statin-induced inhibition of the Rho signalling pathway activates PPAR α and induces HDL-apoAI. J Clin Invest 107:1423–1432

    Article  PubMed  CAS  Google Scholar 

  31. McIntosh TJ (1978) The effect of cholesterol on the structure of phosphatidylcholine bilayers. Biochim Biophys Acta 513:43–58

    PubMed  CAS  Google Scholar 

  32. Mossner R, Schulz U, Kruger U, Middel P, Shinner S, Fuzesi L, Neumann C, Reich K (2002) Agonists of peroxisome proliferator-activated receptors γ inhibit cell growth in malignant melanoma. J Invest Dermatol 119:576–582

    Article  PubMed  CAS  Google Scholar 

  33. Neitzel LT, Neitzel CD, Magee KL, Malafe MP (1999) Angiogenesis correlates with metastasis in melanoma. Ann Surg Oncol 6:70–74

    Article  PubMed  CAS  Google Scholar 

  34. Nyguist DA, Watanabe I, Melnykovych G (1992) Alkyllysophospholipid influenced melanoma cell morphology is associated with decreased attachment to basement membrane. Ukr Biokhim Zh 64:76–85

    PubMed  CAS  Google Scholar 

  35. Pineau T, Hudgins RW, Liu L, Chen L, Sher T, Gonzalez FJ, Samid D (1996) Activation of human peroxisome proliferator-activated receptor by the antitumor agent phenylacetate and its analogs. Biochem Pharmacol 52:659–667

    Article  PubMed  CAS  Google Scholar 

  36. Placha W, Gil D, Dembinska-Kiec A, Laidler P (2003) The effect of PPAR γ ligands on the proliferation and apoptosis of human melanoma cells. Melanoma Res 13:447–456

    PubMed  CAS  ISI  Google Scholar 

  37. Rival Y, Benéteau N, Taillandier T, Pezet M, Dupont-Passelaigue E, Patoiseau J-F, Junquéro D, Colpaert FC, Delhon A (2002) PPARα and PPARδ activators inhibit cytokine-induced nuclear translocation of NF-κB and expression of VCAM-1 in EAhy926 endothelial cells. Eur J Pharmacol 435:143–151

    Article  PubMed  CAS  Google Scholar 

  38. Rog T, Pasenkiewicz-Gierula M (2001) Cholesterol effects on the phospholipid condensation and packing in the bilayer: a molecular simulation study. FEBS Lett 502:68–71

    PubMed  CAS  ISI  Google Scholar 

  39. Romanowska-Dixon B, Urbanska K, Elas M, Pajak S, Zygulska-Mach H, Miodonski A (2001) Angiomorphology of the pigmented Bomirski melanoma growing in hamster eye. Ann Anat 183:559–565

    PubMed  CAS  Google Scholar 

  40. Rowinsky EK, Windle JJ, Von Hoff DD (1999) Ras protein farnesyltransferase inhibitors: a strategic target for anticancer therapeutic development. J Clin Oncol 17:3631–3652

    PubMed  CAS  Google Scholar 

  41. Rubins HB, Robins SJ, Collins CL, Anderson JW, Elam MB, Faas FH, Linares EJ, Schaeffer EJ, Schechtman G, Wilt TJ, Wittes J (1999) Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high density lipoprotein cholesterol. Veterans Affairs High Density Lipoprotein Cholesterol Intervention Trial Study. N Engl J Med 341:410–418

    Article  PubMed  CAS  Google Scholar 

  42. Schreck R (1936) Further quantitative methods for the study of transplantable tumors. The growth of R39 sarcoma and Brown–Pierce carcinomas. Am J Cancer 28:345–351

    Google Scholar 

  43. Schroeder F, Gardiner JM (1984) Membrane lipids and enzymes of high- and low-metastatic B16 melanoma variants. Cancer Res 44:3262–3269

    PubMed  CAS  ISI  Google Scholar 

  44. Scislowski PWD, Slominski A, Bomirski A, Zydowo B (1985) Metabolic characterization of three hamster melanoma variants. Neoplasma 32:593–598

    PubMed  CAS  ISI  Google Scholar 

  45. Sherbet GV (1989) Membrane fluidity and cancer metastasis. Exp Cell Biol 57:198–205

    PubMed  CAS  Google Scholar 

  46. Singh RP, Kumar R, Kapur N (2003) Molecular regulation of cholesterol biosynthesis: implications in carcinogenesis. J Environ Pathol Toxicol Oncol 22:75–92

    PubMed  CAS  Google Scholar 

  47. Siperstein MD (1984) Role of cholesterogenesis and isoprenoid synthesis in DNA replication and cell growth. J Lipid Res 25:1462–1468

    PubMed  CAS  Google Scholar 

  48. Siperstein MD, Fagan VM (1964) Deletion of the cholesterol-negative feedback system in liver tumors. Cancer Res 24:1108–1115

    PubMed  CAS  ISI  Google Scholar 

  49. Slominski A, Paus R (1993) Bomirski melanomas: a versatile and powerful model for pigment cell and melanoma research (review). Int J Oncol 2:221–228

    Google Scholar 

  50. Slominski A, Wortsman J, Carlson AJ, Matsuoka LY, Balch CM, Mihm MC (2001) Malignant melanoma. An update. Arch Pathol Lab Med 125:1295–1306

    PubMed  CAS  Google Scholar 

  51. Storme G, Berdel WE, Van Blittersvijk WJ, Bruynel EA, De Bruyne GK, Mareel MM (1985) Antiinvasive effect of racemic 1-O octadecyl-2-O-methylglycero-3- phosphocholine on MO4 mouse fibrosarcoma cells in vitro. Cancer Res 45:351–357

    PubMed  CAS  ISI  Google Scholar 

  52. Varet J, Vincent L, Mirshahi P, Pille JV, Legrand E, Opolon P, Mishal Z, Soria J, Li H, Soria C (2003) Fenofibrate inhibits angiogenesis in vitro and in vivo. Cell Mol Life Sci 60:810–819

    PubMed  CAS  Google Scholar 

  53. Vereb G, Matko J, Vamosi G, Ibrahim SM, Magyar E, Varga S, Szollosi J, Jenei A, Gaspar R Jr, Waldmann TA, Damjanovich S (2000) Cholesterol-dependent clustering of IL-2Ralpha and its colocalization with HLA and CD48 on T lymphoma cells suggest their functional association with lipid rafts. Proc Natl Acad Sci U S A 97:6013–6018

    Article  PubMed  CAS  Google Scholar 

  54. Wulfert E, Boissard G, Legendre C, Baron C (1981) Inhibition of membrane-bound hepatic 3 hydroxy-3 methyl glutaryl CoA reductase as the consequence of altered membrane fluidity. Artery 9:120–131

    PubMed  CAS  ISI  Google Scholar 

Download references

Acknowledgements

This work was partially supported by the Polish State Committee for Scientific Research in year 2002 (grant 3 P05A 053 23 to M.G.) and the Jagiellonian University (grants N-25/CRBW-22/2001, N-25/CRBW-VII-6/2002 to P.M.P.). The authors would also like to thank Prof. Stanislaw Lukiewicz and Dr. Krzysztof Reiss for their helpful advice and inspiring comments and Thu Ho for language correction. The secretarial assistance of Ms. Christine Crawford is also acknowledged.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Maja Grabacka.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Grabacka, M., Placha, W., Plonka, P.M. et al. Inhibition of melanoma metastases by fenofibrate. Arch Dermatol Res 296, 54–58 (2004). https://doi.org/10.1007/s00403-004-0479-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00403-004-0479-y

Keywords

Navigation