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Pentoxifylline Induces Lipolysis and Apoptosis of Human Preadipocytes, Keratinocytes and Fibroblasts In Vitro

  • Lee, Il-Kyu (Department of Family Medicine, Seoul St. Mary's Hospital) ;
  • Choi, Yun-Jung (Department of Family Medicine, Seoul St. Mary's Hospital) ;
  • Shim, In-Sop (Department of Integrative Medicine, The Catholic University of Korea, College of Medicine) ;
  • Kim, Kyung-Soo (Department of Family Medicine, Seoul St. Mary's Hospital) ;
  • Choi, Chang-Jin (Department of Family Medicine, Seoul St. Mary's Hospital)
  • Published : 2010.01.31

Abstract

Pentoxifylline (PTX) has been used for the local reduction of fat tissue in the clinical setting. However, its safety and efficacy have not been proven. The aim of this study was to evaluate the effects of PTX on cell lines established from fat tissue. Newly cultured human preadipocytes and adipocytes from subcutaneous abdominal fat in addition to purchased human lung fibroblasts and keratinocytes were treated with PTX at different concentrations. Cell viability was determined using the Cell counting kit (CCK)-8 assay and lipolysis was evaluated using an Elisa kit. DNA fragmentation, Western blot analysis, Hoechst and Propidium Iodide (PI) staining and fluorescence activated cell scanning analysis were performed to confirm apoptosis. The viability of adipocytes, preadipocytes, keratinocytes and fibroblasts was markedly decreased at concentrations of PTX above 20 mM. Apoptosis was induced at concentrations of PTX over 40 mM in all cell lines. Lipolysis was increased by 60% at concentrations of PTX of 20 mM compared to the control. In conclusion, the results of this study showed that 20 mM of PTX induced lipolysis. At concentrations over 20 mM, PTX reduced the viability of all cells studied including: adipocytes, preadipocytes, fibroblasts and keratinocytes, in a non-specific manner.

Keywords

References

  1. Bolinder, J., Kerckhoffs, D. A., Moberg, E., Hagstrom-Toft, E. and Arner, P. (2000). Rates of skeletal muscle and adipose tissue glycerol release in nonobese and obese subjects. Diabetes. 49, 797-802. https://doi.org/10.2337/diabetes.49.5.797
  2. Brasaemle, D. L., Dolios, G., Shapiro, L. and Wang, R. (2004). Proteomic analysis of proteins associated with lipid droplets of basal and lypolytically stimulated 3T3-L1 adipocytes. J. Biol. Chem. 279, 46835-46842. https://doi.org/10.1074/jbc.M409340200
  3. Coimbra, R., Melbostad, H., Loomis, W., Tobar, M. and Hoyt, D. B. (2005). Phosphodiesterase inhibition decreases nuclear factor-kappaB activation and shifts the cytokine response toward anti-inflammatory activity in acute endotoxemia. J. Trauma 59, 575-582.
  4. Deree, J., Martins, J. O., Melbostad, H., Loomis, W. H. and Coimbra, R. (2008). Insights into the regulation of TNF-alpha production in human mononuclear cells: the effects of non-specific phosphodiesterase inhibition. Clinics (Sao Paulo) 63, 321-328. https://doi.org/10.1590/S1807-59322008000300006
  5. Doerr, T. D. (2007). Lipoplasty of the face and neck. Curr. Opin. Otolaryngol. Head Neck Surg. 15, 228-232. https://doi.org/10.1097/MOO.0b013e32825b0777
  6. Ducloux, D., Bresson-Vautrin, C. and Chalopin J. (2001). Use of pentoxifylline in membranous nephropathy. Lancet 357, 1672-1673. https://doi.org/10.1016/S0140-6736(00)04830-3
  7. Fleischmann, E., Kurz, A., Niedermayr, M., Schebesta, K., Kimberger, O., Sessler, D. I., Kabon, B. and Prager, G. (2005). Tissue oxygenation in obese and non-obese patients during laparoscopy. Obes. Surg. 15, 813-819. https://doi.org/10.1381/0960892054222867
  8. Hauner, H. (2005). Secretory factors from human adipose tissue and their functional role. Proc. Nutr. Soc. 64, 163-169. https://doi.org/10.1079/PNS2005428
  9. Hauner, H., Entenmann, G., Wabitsch, M., Gaillard, D., Ailhaud, G., Negrel, R. and Pfeiffer E. F. (1989). Promoting effect of glucocorticoids on the differentiation of human adipocyte precursor cells cultured in a chemically defined medium. J. Clin Invest. 84, 1663-1670. https://doi.org/10.1172/JCI114345
  10. Hauner, H., Petruschke, T., Russ, M., Röhrig, K. and Eckel, J. (1995). Effects of tumour necrosis factor alpha (TNF alpha) on glucose transport and lipid metabolism of newly-differentiated human fat cells in cell culture. Diabetologia. 38, 764-771. https://doi.org/10.1007/s001250050350
  11. Hosogai, N., Fukuhara, A., Oshima, K., Miyata, Y., Tanaka, S., Segawa, K., Furukawa, S., Tochino, Y., Komuro, R., Matsuda, M. and Shimomura, I. (2007). Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes. 56, 901-911. https://doi.org/10.2337/db06-0911
  12. Kabon, B., Nagele, A., Reddy, D., Eagon, C., Fleshman, J. W., Sessler, D. I. and Kurz, A. (2004). Obesity decreases perioperative tissue oxygenation. Anesthesiology 100, 274-280. https://doi.org/10.1097/00000542-200402000-00015
  13. Moriau, M., Lavenne-Pardonge, E., Crasborn, L., von Frenckell, R. and Col-Debeys, C. (1995). The treatment of severe or recurrent deep venous thrombosis. Beneficial effect of the co-administration of antiplatelet agents with or without rheological effects, and anticoagulants. Thromb. Res. 78, 469-482. https://doi.org/10.1016/0049-3848(95)00081-2
  14. Morin, C. L., Gayles, E. C., Podolin, D. A., Wei, Y., Xu, M. and Pagliassotti, M. J. (1998). Adipose tissue-derived tumor necrosis factor activity correlates with fat cell size but not insulin action in aging rats. Endocrinology 139, 4998-5005. https://doi.org/10.1210/en.139.12.4998
  15. Moschen, A. R. and Tilg, H. (2008). Nutrition in pathophysiology and treatment of nonalcoholic fatty liver disease. Curr. Opin. Clin. Nutr. Metab. Care 11, 620-625. https://doi.org/10.1097/MCO.0b013e32830b5d09
  16. Prins, J. B., Walker, N. I., Winterford, C. M. and Cameron, D. P. (1994). Human adipocyte apoptosis occurs in malignancy. Biochem. Biophys. Res. Commun. 205, 625-630. https://doi.org/10.1006/bbrc.1994.2711
  17. Qian, H., Hausman, D. B., Compton, M. M., Martin, R. J., Della-Fera, M. A., Hartzell, D. L. and Baile, C. A. (2001). TNFalpha induces and insulin inhibits caspase 3-dependent adipocyte apoptosis. Biochem. Biophys. Res. Commun. 284, 1176-1183. https://doi.org/10.1006/bbrc.2001.5100
  18. Rauko, P., Sedlak, J., Duraj, J., Szekeres, M. F. and Novotny, L. (1998). Pentoxifylline stimulates drug-induced apoptosis in leukemic cells. Neoplasma 45, 296-300.
  19. Rausch, M. E., Weisberg, S., Vardhana, P. and Tortoriello, D. V. (2008). Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltration. Int. J. Obes. (Lond.) 32, 451-463. https://doi.org/10.1038/sj.ijo.0803744
  20. Rishi, L., Gahlot, S., Kathania, M. and Majumdar, S. (2009). Pentoxifylline induces apoptosis in vitro in cutaneous T cell lymphoma (HuT-78) and enhances FasL mediated killing by upregulating Fas expression. Biochem. Pharmacol. 77, 30-45. https://doi.org/10.1016/j.bcp.2008.09.018
  21. Rotunda, A. M., Avram, M. M. and Avram, A. S. (2005). Cellulite: Is there a role for injectables? Int. J. Obes. (Lond.) 32, 451-463. https://doi.org/10.1038/sj.ijo.0803744
  22. Schandene, L., Vandenbussche, P., Crusiaux, A., Alegre, M. L., Abramowicz, D., Dupont, E., Content, J. and Goldman, M. (1992). Differential effects of pentoxifylline on the production of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) by monocytes and T cells. Immunology 76, 30-34.
  23. Selim, K., Huseyin, C., Ibrahim, K. H., Hasan, B. U., Kazim, U. and Hüseyin, K. (2004). Effect of pentoxifylline on tumor necrosis factor-alpha and interleukin-6 levels in neonatal sepsis. Med. J. Malaysia 59, 391-394.
  24. Snyder, P. B., Esselstyn, J. M., Loughney, K., Wolda, S. L. and Florio, V. A. (2005). The role of cyclic nucleotide phosphodiesterases in the regulation of adipocyte lipolysis. J. Lipid Res. 46, 494-503. https://doi.org/10.1194/jlr.M400362-JLR200
  25. Starnes, H. F. Jr., Warren, R. S., Jeevanandam, M., Gabrilove, J. L., Larchian, W., Oettgen, H. F. and Brennan, M. F. (1988). Tumor necrosis factor and the acute metabolic response to tissue injury in man. J. Clin. Invest. 82, 1321-1325. https://doi.org/10.1172/JCI113733
  26. Strieter, R. M., Remick, D. G., Ward, P. A., Spengler, R. N., Lynch, J. P. 3rd., Larrick, J. and Kunkel, S. L. (1988). Cellular and molecular regulation of tumor necrosis factor-alpha production by pentoxifylline. Biochem. Biophys. Res. Commun. 155, 1230-1236. https://doi.org/10.1016/S0006-291X(88)81271-3
  27. van Harmelen, V., Skurk, T., Röhrig, K., Lee, Y. M., Halbleib, M., Aprath-Husmann, I. and Hauner, H. (2003). Effect of BMI and age on adipose tissue cellularity and differentiation capacity in women. Int. J. Obes. Relat. Metab. Disord. 27, 889- 895. https://doi.org/10.1038/sj.ijo.0802314
  28. Ward, A. and Clissold, S. P. (1987). A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy. Drugs 34, 50-97. https://doi.org/10.2165/00003495-198734010-00003
  29. Wikimedia Foundation, Inc: Mesotherapy [internet] Wikimedia Foundation; c2001-2009. [cited 2009 Feb 2]. Available from:http://en.wikipedia.org/wiki/Mesotherapy.
  30. Yalniz, M., Bahcecioglu, I. H., Kuzu, N., Celebi, S., Ataseven, H., Ustündağ, B., Ozercan, I. H. and Sahin, K. (2007). Amelioration of steatohepatitis with pentoxifylline in a novel nonalcoholic steatohepatitis model induced by high-fat diet. Dig. Dis. Sci. 52, 2380-2386. https://doi.org/10.1007/s10620-006-9194-1
  31. Yang, X., Jansson, P. A., Nagaev, I., Jack, M. M., Carvalho, E., Sunnerhagen, K. S., Cam, M. C., Cushman, S. W. and Smith, U. (2004). Evidence of impaired adipogenesis in insulin resistance. Biochemical and biophysical research communications. Biochem. Biophys. Res. Commun. 317, 1045-1051. https://doi.org/10.1016/j.bbrc.2004.03.152
  32. Ye, J. (2009). Emerging role of adipose tissue hypoxia in obesity and insulin resistance. Int. J. Obes. (Lond.) 33, 54-66. https://doi.org/10.1038/ijo.2008.229
  33. Zabel, P., Schade, F. U. and Schlaak, M. (1993). Inhibition of endogenous TNF formation by pentoxifylline. Immunobiology 187, 447-463. https://doi.org/10.1016/S0171-2985(11)80356-6

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