Journal of Neuro-Oncology

, Volume 139, Issue 1, pp 43–50 | Cite as

Evidence for intrathecal sodium butyrate as a novel option for leptomeningeal metastasis

  • Hidemitsu Nakagawa
  • Yoshihiro Yui
  • Satoru Sasagawa
  • Kazuyuki Itoh
Laboratory Investigation



The prognosis for leptomeningeal metastasis (LM) remains extremely poor regardless of intrathecal chemotherapy with various drugs, and thus, new treatments are necessary. Butyrate is an endogenous 4-carbon saturated fatty acid, has been investigated as an anti-tumor agent because of its multiple suppressive effects on several tumors. In this study, we investigated the cellular basis of sodium butyrate (SB), a sodium salt compound of butyrate, in vitro and evaluated the clinical potential of intrathecal SB administration for LM in vivo.


We examined SB’s effects on Walker 256 rat mammary tumor cells with regard to cytotoxicity, cell morphology, colony formation, migration, and invasion. We also examined SB’s neurotoxicity for primary neurons and primary astrocytes. We finally evaluated the potency of continuous intrathecal SB administration in rats with intrathecally transplanted breast tumors as an LM model.


Physiological SB concentrations (2–4 mM) induced growth suppression, morphological changes, and inhibition of migration and invasion, but did not exhibit neurotoxic effects on primary neurons and astrocytes. Continuous intrathecal SB administration in a rat LM model significantly increased survival periods with little neurotoxicity.


Continuous intrathecal SB administration significantly improved prognoses in a rat LM model, which suggests that SB is a promising therapy for LM.


Intrathecal administration Sodium butyrate Neurotoxicity Leptomeningeal metastasis 



Cytosine arabinoside




Dulbecco modified essential medium


Fetal bovine serum


Minimum essential medium




Phosphate buffer saline

Supplementary material

11060_2018_2852_MOESM1_ESM.jpg (1 mb)
Figure S1. Surgical osmotic pump implantation into the medullary cavity. a. The osmotic mini-pump. Bar = 1 cm. b. Schematic of osmotic mini-pump implantation (JPG 1041 KB)
11060_2018_2852_MOESM2_ESM.jpg (414 kb)
Figure S2. Effect of MTX treatment on neuronal cells and astrocyte. a. Neuron viability in the presence of MTX. We treated primary isolated neurons with various MTX concentrations and observed cell viability. b. Astrocyte viability in the presence of MTX. We treated primary isolated astrocytes with various MTX concentrations and observed cell viability. *: P < 0.01; abbreviations: MTX, methotrexate (JPG 414 KB)
11060_2018_2852_MOESM3_ESM.jpg (1.7 mb)
Figure S3. Histological confirmation of SB-induced brain damage. An SB-treated rat brain was sectioned and stained with hematoxylin and eosin or with the Klüver-Barrera method. No obviously damaged regions were observed. Bar = 50 µm. Abbreviation: SB, sodium butyrate (JPG 1712 KB)


  1. 1.
    Taillibert S, Laigle-Donadey F, Chodkiewicz C, Sanson M, Hoang-Xuan K, Delattre J-Y (2005) Leptomeningeal metastases from solid malignancy: a review. J Neurooncol 75(1):85–99. CrossRefPubMedGoogle Scholar
  2. 2.
    Le Rhun E, Taillibert S, Chamberlain MC (2017) Neoplastic meningitis due to lung, breast, and melanoma metastases. Cancer Control 24(1):22–32CrossRefPubMedGoogle Scholar
  3. 3.
    Taillibert S, Hildebrand J (2006) Treatment of central nervous system metastases: parenchymal, epidural, and leptomeningeal. Curr Opin Oncol 18(6):637–643. CrossRefPubMedGoogle Scholar
  4. 4.
    Nakagawa H, Murasawa A, Kubo S et al (1992) Diagnosis and treatment of patients with meningeal carcinomatosis. J Neurooncol 13(1):81–89CrossRefPubMedGoogle Scholar
  5. 5.
    Grewal J, Saria MG, Kesari S (2012) Novel approaches to treating leptomeningeal metastases. J Neurooncol 106(2):225–234. CrossRefPubMedGoogle Scholar
  6. 6.
    Groves MD (2010) New strategies in the management of leptomeningeal metastases. Arch Neurol 67(3):305–312. CrossRefPubMedGoogle Scholar
  7. 7.
    Roth P, Weller M (2015) Management of neoplastic meningitis. Chin Clin Oncol 4(2):26. PubMedGoogle Scholar
  8. 8.
    Fields MM (2013) How to recognize and treat neoplastic meningitis. J Adv Pract Oncol 4(3):155–160PubMedPubMedCentralGoogle Scholar
  9. 9.
    Blaney SM, Balis FM, Berg S et al (2005) Intrathecal mafosfamide: a preclinical pharmacology and phase I trial. J Clin Oncol 23(7):1555–1563. CrossRefPubMedGoogle Scholar
  10. 10.
    Blaney SM, Heideman R, Berg S et al (2003) Phase I clinical trial of intrathecal topotecan in patients with neoplastic meningitis. J Clin Oncol 21(1):143–147. CrossRefPubMedGoogle Scholar
  11. 11.
    Sampson JH, Archer GE, Villavicencio AT et al (1999) Treatment of neoplastic meningitis with intrathecal temozolomide. Clin Cancer Res 5(5):1183–1188PubMedGoogle Scholar
  12. 12.
    Nakagawa H, Miyahara E, Suzuki T, Wada K, Tamura M, Fukushima Y (2005) Continuous intrathecal administration of 5-fluoro-2′-deoxyuridine for the treatment of neoplastic meningitis. Neurosurgery 57(2):266–280CrossRefPubMedGoogle Scholar
  13. 13.
    Nakagawa H, Yoshioka K, Miyahara E, Fukushima Y, Tamura M, Itoh K (2005) Intrathecal administration of Y-27632, a specific rho-associated kinase inhibitor, for rat neoplastic meningitis. Mol Cancer Res 3(8):425–433. CrossRefPubMedGoogle Scholar
  14. 14.
    Pryde SE, Duncan SH, Hold GL, Stewart CS, Flint HJ (2002) The microbiology of butyrate formation in the human colon. FEMS Microbiol Lett 217(2):133–139CrossRefPubMedGoogle Scholar
  15. 15.
    Scharlau D, Borowicki A, Habermann N et al (2009) Mechanisms of primary cancer prevention by butyrate and other products formed during gut flora-mediated fermentation of dietary fibre. Mutat Res 682(1):39–53. CrossRefPubMedGoogle Scholar
  16. 16.
    Encarnação JC, Abrantes AM, Pires AS, Botelho MF (2015) Revisit dietary fiber on colorectal cancer: butyrate and its role on prevention and treatment. Cancer Metastasis Rev 34(3):465–478. CrossRefPubMedGoogle Scholar
  17. 17.
    Hamer HM, Jonkers D, Venema K, Vanhoutvin S, Troost FJ, Brummer R-J (2007) Review article: the role of butyrate on colonic function. Aliment Pharmacol Ther 27(2):104–119. CrossRefPubMedGoogle Scholar
  18. 18.
    Davie JR (2003) Inhibition of histone deacetylase activity by butyrate. J Nutr 133(7 Suppl):2485S–2493SCrossRefPubMedGoogle Scholar
  19. 19.
    Damaskos C, Valsami S, Kontos M et al (2017) Histone deacetylase inhibitors: an attractive therapeutic strategy against breast cancer. Anticancer Res 37(1):35–46. CrossRefPubMedGoogle Scholar
  20. 20.
    Zhang J, Yi M, Zha L et al (2016) Sodium butyrate induces endoplasmic reticulum stress and autophagy in colorectal cells: implications for apoptosis. PLoS ONE 11(1):e0147218. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Hara I, Miyake H, Hara S, Arakawa S, Kamidono S (2000) Sodium butyrate induces apoptosis in human renal cell carcinoma cells and synergistically enhances their sensitivity to anti-Fas-mediated cytotoxicity. Int J Oncol 17(6):1213–1218PubMedGoogle Scholar
  22. 22.
    Katzenmaier E-M, André S, Kopitz J, Gabius H-J (2014) Impact of sodium butyrate on the network of adhesion/growth-regulatory galectins in human colon cancer in vitro. Anticancer Res 34(10):5429–5438PubMedGoogle Scholar
  23. 23.
    Farrow B, Rychahou P, O’Connor KL, Evers BM (2003) Butyrate inhibits pancreatic cancer invasion. J Gastrointest Surg 7(7):864–870CrossRefPubMedGoogle Scholar
  24. 24.
    Demary K, Wong L, Spanjaard RA (2001) Effects of retinoic acid and sodium butyrate on gene expression, histone acetylation and inhibition of proliferation of melanoma cells. Cancer Lett 163(1):103–107CrossRefPubMedGoogle Scholar
  25. 25.
    Engelhard HH, Duncan HA, Kim S, Criswell PS, Van Eldik L (2001) Therapeutic effects of sodium butyrate on glioma cells in vitro and in the rat C6 glioma model. Neurosurgery 48(3):616–625CrossRefPubMedGoogle Scholar
  26. 26.
    Conway RM, Madigan MC, Billson FA, Penfold PL (1998) Vincristine- and cisplatin-induced apoptosis in human retinoblastoma. Potentiation by sodium butyrate. Eur J Cancer 34(11):1741–1748CrossRefPubMedGoogle Scholar
  27. 27.
    Lauricella M, Calvaruso G, Giuliano M et al (2000) Synergistic cytotoxic interactions between sodium butyrate, MG132 and camptothecin in human retinoblastoma Y79 cells. Tumour Biol 21(6):337–348. doi:30139CrossRefPubMedGoogle Scholar
  28. 28.
    Sankaranarayanan K, von Duyn A, Loos MJ, Meschini R, Natarajan AT (2000) Effects of sodium butyrate on X-ray and bleomycin-induced chromosome aberrations in human peripheral blood lymphocytes. Genet Res 56(2–3):267–276Google Scholar
  29. 29.
    Stoilov L, Darroudi F, Meschini R, van der Schans G, Mullenders LH, Natarajan AT (2000) Inhibition of repair of X-ray-induced DNA double-strand breaks in human lymphocytes exposed to sodium butyrate. Int J Radiat Biol 76(11):1485–1491CrossRefPubMedGoogle Scholar
  30. 30.
    Vernia P, Fracasso PL, Casale V et al (2000) Topical butyrate for acute radiation proctitis: randomised, crossover trial. Lancet 356(9237):1232–1235CrossRefPubMedGoogle Scholar
  31. 31.
    Maggio A, Magli A, Rancati T et al (2014) Daily sodium butyrate enema for the prevention of radiation proctitis in prostate cancer patients undergoing radical radiation therapy: results of a multicenter randomized placebo-controlled dose-finding phase 2 study. Int J Radiat Oncol Biol Phys 89(3):518–524. CrossRefPubMedGoogle Scholar
  32. 32.
    Krokowicz L, Stojcev Z, Kaczmarek BF et al (2014) Microencapsulated sodium butyrate administered to patients with diverticulosis decreases incidence of diverticulitis—a prospective randomized study. Int J Colorectal Dis 29(3):387–393. CrossRefPubMedGoogle Scholar
  33. 33.
    Raqib R, Sarker P, Mily A et al (2012) Efficacy of sodium butyrate adjunct therapy in shigellosis: a randomized, double-blind, placebo-controlled clinical trial. BMC Infect Dis 12(1):111. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Ziemka-Nalecz M, Jaworska J, Sypecka J, Polowy R, Filipkowski RK, Zalewska T (2016) Sodium butyrate, a histone deacetylase inhibitor, exhibits neuroprotective/neurogenic effects in a rat model of neonatal hypoxia-ischemia. Mol Neurobiol. PubMedPubMedCentralGoogle Scholar
  35. 35.
    Jaworska J, Ziemka-Nalecz M, Sypecka J, Zalewska T (2017) The potential neuroprotective role of a histone deacetylase inhibitor, sodium butyrate, after neonatal hypoxia-ischemia. J Neuroinflammation 14(1):34. CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Li H, Sun J, Wang F et al (2016) Sodium butyrate exerts neuroprotective effects by restoring the blood-brain barrier in traumatic brain injury mice. Brain Res 1642:70–78. CrossRefPubMedGoogle Scholar
  37. 37.
    Asou H, Hirano S, Kohsaka S (1989) Changes in ganglioside composition and morphological features during the development of cultured astrocytes from rat brain. Neurosci Res 6(4):369–375CrossRefPubMedGoogle Scholar
  38. 38.
    Donohoe DR, Collins LB, Wali A, Bigler R, Sun W, Bultman SJ (2012) The Warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation. Mol Cell 48(4):612–626. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324(5930):1029–1033. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of NeurosurgeryNozaki Tokushukai HospitalDaitoJapan
  2. 2.Research InstituteNozaki Tokushukai HospitalDaitoJapan

Personalised recommendations