Valpro ic Acid –  Anti epileptics with Antine oplastic Effects


Authors: P. Cahová;  H. Ošlejšková
Authors‘ workplace: Klinika dětské neurologie LF MU a FN Brno
Published in: Cesk Slov Neurol N 2009; 72/105(3): 217-221
Category: Review Article

Overview

Valpro ic acid is a bro ad- spectrum anti epileptic drug with low toxicitiy profile. It has been marketed since 1967, firstly bro ught o ut in France. Its importance in the clinical practice is a ugmented by the use in other indicati ons. Valpro ic acid is also prescribed in the tre atment of he adache, affective disorders and spinal muscular atrophy. Recently, valpro ic acid has appe ared in the focus of attenti on in the ne uro oncology fi eld as well. As histone de acetylase inhibitor it ca uses hyperacetylati on and reexpressi on of growth regulatory genes and as a consequence induces apoptosis. In preclinical studi es it has been proved that valpro ic acid is able to inhibit cell proliferati on and migrati on and incre ases the imunogenicity of tumoral cells. Brain tumors are often accompani ed by the symptomatic epileptic seizures depending on the histo­logy and localisati on of the tumor. The epilepsy is not seldom farmacoresistant. Being able to take advantage of anti epileptic and antitumoral effect of valpro ic effect, we get a specific opti on in the tre atment of symptomatic seizures in brain tumors. With o ur present knowledge the indicati on of valpro ic acid as an anti epileptic drug with antitumoral effects needs more investigati ons.

Key words:
valpro ic acid –  anti epileptic drug –  oncology


Sources

1. Löscher W. Basic pharmacology of valpro ate: a revi ew after 35 ye ars of clinical use for the tre atment of epilepsy. CNS Drugs 2002; 16(10): 669– 694.

2. Sýkora P. Li ečba epileptických syndrómov v detskom veku s nepri aznivo u prognózo u. Ne urol pro praxi 2007; 8(2): 91– 93.

3. Komárek V. Léčba věkově vázaných epileptických syndromů s příznivější prognózo u. Ne urol pro praxi 2007; 8(2): 87– 90.

4. Komárek V. Léčba epileptických syndromů u dětí. Cesk Slov Ne urol N 2007; 70/ 103(5): 473– 487.

5. Guerrini R. Valpro ate as a mainstay of therapy for pedi atric epilepsy. Paedi atr Drugs 2006; 8(2): 113– 129.

6. Burton BS. On the propyl derivatives and decompositi on products of aceto acetic ester. Am Chem J 1882; 3: 385– 395.

7. Me uni er H, Carraz G, Me uni er Y, Eymard P, Aimard M.Propri étés pharmacodynamiques de l’acide n- dipropylacétique. Thérapi e 1963; 18: 435– 438.

8. Wirth B, Brichta L, Hahnen E. Spinal muscular atrophy: from gene to therapy. Semin Pedi atr Ne urol 2006; 13(2): 121– 131.

9. Brichta L, Hofmann Y, Hahnen E, Si ebsehnrubl FA, Raschke H, Blumcke I et al. Valpro ic acid incre ases the SMN2 protein level: a well‑known drug as a potenti al therapy for spinal muscular atrophy. Hum Mol Genet 2003; 12(19): 2481– 2489.

10. Yurekli VA, Akhan G, Kutluhan S, Uzar E, Koyuncuoglu HR, Gultekin F. The effect of sodi um valpro ate on chronic daily he adache and its subgro ups. J He adache Pain 2008; 9(1): 37– 41.

11. Fujita M, Fujiwara J, Maki T, Shigeta M, Shibasaki K,Takahashi N et al. The efficacy of sodi um valpro ate and MRA fading in confusi onal migraine. Brain Dev 2007; 29(3): 178– 181.

12. Reiter PD, Nickisch J, Merritt G. Efficacy and tolerability of intraveno us valpro ic acid in acute adolescent migraine. He adache 2005; 45(7): 899– 903.

13. Blaheta RA, Cinatl J jr. Anti‑tumor mechanisms of valpro ate: a novel role for an old drug. Med Res Rev 2002; 22(5): 492– 511.

14. Furchert SE, Lanvers- Kaminsky C, Juurgens H, Jung M,Lo idl A, Frühwald MC. Inhibitors of histone de acetylases as potenti al therape utic to ols for high risk embryonal tumors of the nervo us system of childho od. Int J Cancer 2007; 120(8): 1787– 1794.

15. Dragunow M, Greenwo od JM, Cameron RE, Narayan PJ, O’Carroll SJ, Pe arson AG et al. Valpro ic acid induces caspase 3- medi ated apoptosis in microgli al cells. Ne urosci ence 2006; 140(4): 1149– 1156.

16. Li XN, Shu Q, Men- Feng Su J, Perlaky L, Blaney SM, La u CC. Valpro ic acid induces growth arrest, apoptosis, and senescence in medulloblastomas by incre asing histone hyperacetylati on and regulating expressi on of p21Cip1, CDK4, and CMYC. Mol Cancer Ther 2005; 4(12): 1912– 1922.

17. Shu Q, Antalffy B, Su JM, Adesina A, Ou CN, Pi etsch T et al. Valpro ic acid prolongs survival time of severe combined immunodefici ent mice be aring intracerebellar orthotopic medulloblastoma xenografts. Clin Cancer Res 2006; 12(15): 4687– 4694.

18. Campha usen K, Cerna D, Scott T, Spro ull M, Burgan WE, Cerra MA et al. Enhancement of in vitro and in vivo tumor cell radi osensitivity by valpro ic acid. Int J Cancer 2005; 114(3): 380– 386.

19. Knüpfer MM, Hernáiz- Dri ever P, Poppenborg H, Wolff JE, Cinatl J. Valpropic acid inhibits proliferati on and changes expressi on of CD44 and CD56 of malignant gli oma cells in vitro. Anticancer Res 1998; 18(5A): 3585– 3590.

20. Knüpfer MM, Pulzer F, Schindler I, Hernáiz- Dri ever P,Knupfer H, Keller E. Different effects of valpro ic acid on proliferati on and migrati on of malignant gli oma cells in vitro. Anticancer Res 2001; 21(1A): 347– 352.

21. Dri ever PH, Knüpfer MM, Wolff JE. Valpro ic acid for the tre atment of pedi atric malignant gli oma. Klin Padi atr 1999; 211(4): 323– 328.

22. Edvardsen K, Chen W, Rucklidge G, Walsch FS, Obrink B, Bock E. Transmembrane ne ural cell adhesi on molecule (NCAM), but not glycosyl- phosphatidylinositol- anchored N- CAM, down- regulates secreti on of matrix metalloproteinases. Proc Nat Acad Sci USA 1993; 90(24): 1146– 11467.

23. Fantini J, Guo XJ, Marvaldi J, Ro ugon G. Suramin inhibits proliferati on of rat gli oma cells and alters NCAM cell surface expressi on. Int J Cancer 1990; 45(3): 554– 561.

24. Cinatl J jr, Cinatl J, Scholz M, Dri ever PH, Henrich D,Kabickova H et al. Antitumor activity of sodi um valpro ate in cultures of human ne uroblastoma cells. Anticancer Drugs 1996; 7(7): 766– 773.

25. Smith S, Stern A. The effect of aromatic CoA esters on fatty acid synthetase: bi osynthesis of w- phenyl fatty acids. Arch Bi ochem Bi ophys 1983; 222(1): 259– 265.

26. Prasanna P, Thiba ult A, Li u L, Samid D. Lipid metabolism as a target for brain cancer therapy: synergistic aktivity of lovastatin and sodi um phenylacetate against human gli oma cells. J Ne urochem 1996; 66(2): 710– 716.

27. Chen G, Yu an P, Hawver DB, Potter WZ, Manji HK. Incre ase in AP- 1 transcripti on factor DNA binding activity by valpro ic acid. Ne uropsychopharmacology 1997; 16(3): 238– 245.

28. Dri ever PH, Wagner S, Hofstädter F, Wolff JE. Valpro ic acid induces differenti ati on of a supratentori al primitive ne uroectodermal tumor. Pedi atr Hematol Oncol 2004; 21(8): 743– 751.

29. Ki eslich M, Schwabe D, Cinatl J jr, Dri ever PH. Incre ase of fetal hemoglobin synthesis indicating differenti ati on inducti on in children receiving valpro ic acid. Pedi atr Hematol Oncol 2003; 20(1): 15– 22.

30. Maso udi A, Elopre M, Amini E, Nagel ME, Ater JL, Gopalakrishnan V et al. Influence of valpro ic acid on o utcome of high grade gli omas in children. Anticancer Res 2008; 28(4C): 2437– 2442.

31. Kuendgen A, Strupp C, Aivado M, Bernhardt A, Hildebrandt B, Haas R et al. Tre atment of myelodysplastic syndromes with valpro ic acid alone or in combinati on with all‑trans retino ic acid. Blo od 2004; 104(5): 1266– 1269.

32. Kuendgen A, Schmid M, Schlenk R, Knipp S, Hildebrandt B, Steidl Ch et al. The histone de acetylase (HDAC) inhibitor valpro ic acid as monotherapy or in combinati on with all‑trans retino ic acid in pati ents with acute myelo id le ukemi a. Cancer 2006; 106(1): 112– 119.

33. Kaiser M, Zavrski I, Sterz J, Jakob Ch, Fleissner C, Kloetzel PM et al. The effects of the histone de acetylase inhibitor valpro ic acid on cell cycle, growth suppressi on and apoptosis in multiple myeloma. Haematologica 2006; 91(2): 248– 251.

34. Greenblatt DY, Vaccaro AM, Jaskula- Sztul R, Ning L,Haymart M, Kunnimalaiyaan M et al. Valpro ic acid activates Notch- 1 signaling and regulates the ne uroendocrine phenotype in carcino id cancer cells. Oncologist 2007; 12(8): 942– 951.

35. Greenblatt DY, Cayo MA, Adler JT, Ning L, Haymart MR, Kunnimalaiyaan M et al. Valpro ic acid activates Notch1 signaling and induces apoptosis in medullary thyro id cancer cells. Ann Surg 2008; 247(6): 1036– 1040.

36. Sami S, Höti N, Xu HM, Shen Z, Hu ang X. Valpro ic acid inhibits the growth of cervical cancer both in vitro and in vivo. J Bi ochem 2008; 144(3): 357– 362.

37. Jones J, Bentas W, Blaheta RA, Makarevic J, Hudak L,Wedel S et al. Modulati on of adhesi on of colon and pancre atic cancer cells by the histone de acetylase inhibitor valpro ic acid. Int J Mol Med 2008; 22(3): 293– 299.

38. Ward MM, Barbaro NM, Laxer KD, Rampil IJ. Pre operative valpro ate administrati on does not incre ase blo od loss during temporal lobectomy. Epilepsi a 1996; 37(1): 98– 101.

39. Verotti A, Greco R, Matera V, Altobelli E, Morgese G,Chi arelli F. Platelet co unt and functi on in children receiving sodi um valpro ate. Pedi atr Ne urol 1999; 21(3): 611– 614.

40. Koenig S, Gerstner T, Keller A, Teich M, Longin E,Dempfle CE. High incidence of valpro ate‑induced co agulati on disorders in children receiving valpro ic acid: a prospective study. Blo od Co agul Fibrinolysis 2008; 19(5): 375– 382.

41. Nasreddine W, Beydo un A. Valpro ate‑induced thrombocytopeni a: a prospective monotherapy study. Epilepsi a 2008; 49(3): 438– 445.

42. Teich M, Longin E, Dempfle CE, König S. Factor XIII defici ency associ ated with valpro ate tre atment. Epilepsi a 2004; 42(2): 187– 189.

43. Cannizzaro E, Albisetti M, Wohlrab G, Schmugge M.Severe bleeding complicati ons during anti epileptic tre atment with valpro ic acis in children. Ne uropedi atrics 2007; 38(1): 42– 45.

44. Carney BT, Minter CL. Is operative blo od loss associ ated with valpro ic acid? Analysis of bilateral femoral oste otomy in children with total involvement cerebral palsy. J Pedi atr Orthop 2005; 25(3): 283– 285.

45. Rocca A, Minucci S, Tosti G, Croci D, Contegno F,Ballarini M et al. A phase I– II study of the histone de acetylase inhibitor valpro ic acid plus chemo immunotherapy in pati ents with advanced melanoma. Br J Cancer 2009; 100(1): 28– 36.

Labels
Paediatric neurology Neurosurgery Neurology

Article was published in

Czech and Slovak Neurology and Neurosurgery

Issue 3

2009 Issue 3

Most read in this issue
Login
Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.

Login

Don‘t have an account?  Create new account