Inhibitors of enzymes involved in lipidic metabolism with antiproliferative activity

Prostate cancer is one of the most common cancers in men, and the second cause of cancer leading to death. Although in recent years, the mortality rate from this cancer declined significantly, it remains too high. Considerable efforts have been made to develop new therapies targeting receptor of growth factors or anti-angiogenic. However, studies of the influence of the metabolism of cancer cells on tumor progression are rare. However, the relationship between metabolism and cell proliferation has been described quite a long time ago. A first observation date from the 1930s, made by Otto Warburg showed that cancer cells with a high proliferative rate, have an increased need for glucose and showed a disturbed metabolism. Another feature of metabolic cancer cells is the increased “de novo” synthesis  of fatty acids (“de novo” lipogenesis). Most normal tissues use circulating fatty acids for the synthesis of membranes or as an energy source. However, cancer cells use the fatty acids synthesized de novo from carbohydrates. The consequence of this particular use of fatty acids is demonstrated by the differential composition of cell membranes, and signaling lipid in cancer cells. This lipogenesis increase was demonstrated by the increase of the activity of lipogenic enzymes (FAS, SCD-1, …) observed in cancers.

Studies based on the use of chemical inhibitors of Fatty Acid Synthase (FAS), a key enzyme of lipogenesis, have shown that inhibition of its activity leads to decreased proliferation and increased apoptosis cancer cells. [1-5]

Furthermore, it has been shown that pharmacological inhibition of stearoyl coenzyme A desaturase (SCD-1, an enzyme that catalyzes the conversion of saturated fatty acids into mono-unsaturated fatty acids) leads to a decrease of human prostate tumor cell proliferation . [6.7]

As synthetic organic and bioorganic chemists a (LCBO-UNIMA) and allow us to design and prepare new molecules with potential lipidic enzyme inhibitor activity.

References :

 [1] O.Warburg. Ueber den stoffwechsel der tumoren. London : Constable, 1930. [2] O. Warburg,  Science 1956, 123, 309–314.  [3] G. Medes, A. Thomas, S. Weinhouse, Cancer Res. 1953, 13 27-29. [4] F.P. Kuhajda, K. Jenner, F.D. Wood, R.A. Hennigar, L.B. Jacobs, J.D. Dick, G.R. Pasternack, PNAS 1994, 91, 6379-6383. [5] F. P. Kuhajda.  Nutrition, 2000,  16: 202–208. [6] Z. Benfodda, V. Fritz, G. Rodier, C. Henriquet, F. Iborra, C. Avances, Y. Allory, A. Delataille, S. Culine, H. Blancou, J-P. Cristol, F. Michel, C. Sardet, L. Fajas. Mol Cancer Ther. 2010, 9(6) 1740-1754. [7] N. Scaglia, RA. Igal, Int J Oncol. 2008, 33, 839–850.

Collaborations :

Dr Lluis FAJAS (IRCM, INSERM U 896, Montpellier),

Dr Gilles LABESSE, Dr Jean-François GUICHOU (CBS- CNRS UMR 5048 – UM 1 – INSERM U 554)

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