Skip to main content

Advertisement

SpringerLink
Log in

The enhanced apoptosis and antiproliferative response to combined treatment with valproate and nicotinamide in MCF-7 breast cancer cells

  • Research Article
  • Published:
Tumor Biology

Abstract

Acetylation of histone is a major player in epigenetic modifications, resulting in open chromatin structures and, hence, permissive conditions for transcription-factor recruitment to the promoters, followed by initiation of transcription. Histone deacetylase inhibitors arrest cancer cell growth and cause apoptosis with low toxicity thereby constituting a promising treatment for cancer. In this study, we examined the antiproliferative effects of valproate with a combination of nicotinamide in the MCF-7 cell line. MCF-7 was treated with various concentrations of valproate. The MTT assay showed that the viability of MCF-7 cells was inhibited and the cell activity was decreased. Viability percent of valproate and nicotinamide combined treatment cells (28 ± 2) was 1.78 times increased compared with the valproate-alone (0.5 mM) treated cells (50 ± 2). Colony formation in soft agar indicated that valproate at 0.3 mM, when used alone, weakly suppressed proliferation of cells (82 ± 3) and the combination treatment of valproate + nicotinamide strongly suppressed cell proliferation (51 ± 3). The flow cytometric and microscopic analyses of HDACI combined with treated cells indicated strong apoptosis induction and nuclear morphological alterations greater than those of valproate alone. Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) analysis confirmed the efficiency of the HDAC inhibitor combination, revealing the effectively upregulated p16 and p21. Furthermore, to investigate the role of acetyl-histone H3 levels, western blot analyses have been performed and high levels of acetylated histone H3 were detected in valproate- and nicotinamide-treated cells. These results suggest that the combination treatment of valproate with nicotinamide exerts significant antitumor activity and could be a promising therapeutic candidate to treat human breast cancer.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Alao JP, Stavropoulou AV, Lam EW, Coombes RC, Vigushin DM. Histone deacetylase inhibitor, trichostatin A induces ubiquitin-dependent cyclin D1 degradation in MCF-7 breast cancer cells. Mol Cancer. 2006;5:8.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  2. Bozkurt E, Atmaca H, Kisim A, Uzunoglu S, Uslu R, Karaca B. Effects of Thymus serpyllum extract on cell proliferation, apoptosis and epigenetic events in human breast cancer cells. Nutr Cancer. 2012;64(8):1245–50.

    Article  PubMed  Google Scholar 

  3. Carew JS, Giles FJ, Nawrocki ST. Histone deacetylase inhibitors: mechanisms of cell death and promise in combination cancer therapy. Cancer lett. 2008;269(1):7–17.

    Article  PubMed  CAS  Google Scholar 

  4. Ageberg M, Rydstrom K, Relander T, Drott K. The histone deacetylase inhibitor valproic acid sensitizes diffuse large B-cell lymphoma cell lines to CHOP-induced cell death. Am J Transl Res. 2013;5(2):170–83.

    PubMed Central  PubMed  CAS  Google Scholar 

  5. Hsia DA, Tepper CG, Pochampalli MR, Hsia EY, Izumiya C, Huerta SB, et al. KDM8, a H3K36me2 histone demethylase that acts in the cyclin A1 coding region to regulate cancer cell proliferation. Proc Natl Acad Sci U S A. 2010;107(21):9671–6.

    Article  PubMed Central  PubMed  Google Scholar 

  6. Ellis L, Atadja PW, Johnstone RW. Epigenetics in cancer: targeting chromatin modifications. Mol Cancer Ther. 2009;8(6):1409–20.

    Article  PubMed  CAS  Google Scholar 

  7. Ellis L, Pili R. Histone deacetylase inhibitors: advancing therapeutic strategies in hematological and solid malignancies. Pharmaceuticals (Basel). 2010;3(8):2411–69.

    Article  CAS  Google Scholar 

  8. Emanuele S, Lauricella M, Tesoriere G. Histone deacetylase inhibitors: apoptotic effects and clinical implications (review). Int J Oncol. 2008;33(4):637–46.

    PubMed  CAS  Google Scholar 

  9. Ward CS, Eriksson P, Izquierdo-Garcia JL, Brandes AH, Ronen SM. HDAC inhibition induces increased choline uptake and elevated phosphocholine levels in MCF7 breast cancer cells. PLoS One. 2013;8(4):e62610.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  10. Jeong JB, Choi J, Lou Z, Jiang X, Lee SH. Patchouli alcohol, an essential oil of Pogostemon cablin, exhibits anti-tumorigenic activity in human colorectal cancer cells. Int Immunopharmacol. 2013;16(2):184–90.

    Article  PubMed  CAS  Google Scholar 

  11. Jung M, Kozikowski A, Dritschilo A. Rational design and development of radiation-sensitizing histone deacetylase inhibitors. Chem biodivers. 2005;2(11):1452–61.

    Article  PubMed  CAS  Google Scholar 

  12. Noro R, Miyanaga A, Minegishi Y, Okano T, Seike M, Soeno C, et al. Histone deacetylase inhibitor enhances sensitivity of non-small-cell lung cancer cells to 5-FU/S-1 via down-regulation of thymidylate synthase expression and up-regulation of p21(waf1/cip1) expression. Cancer Sci. 2010;101(6):1424–30.

    Article  PubMed  CAS  Google Scholar 

  13. Souto JA, Conte M, Alvarez R, Nebbioso A, Carafa V, Altucci L, et al. Synthesis of benzamides related to anacardic acid and their histone acetyltransferase (HAT) inhibitory activities. ChemMedChem. 2008;3(9):1435–42.

    Article  PubMed  CAS  Google Scholar 

  14. Bug G, Ritter M, Wassmann B, Schoch C, Heinzel T, Schwarz K, et al. Clinical trial of valproic acid and all-trans retinoic acid in patients with poor-risk acute myeloid leukemia. Cancer. 2005;104(12):2717–25.

    Article  PubMed  CAS  Google Scholar 

  15. Franci G, Miceli M, Altucci L. Targeting epigenetic networks with polypharmacology: a new avenue to tackle cancer. Epigenomics. 2010;2(6):731–42.

    Article  PubMed  CAS  Google Scholar 

  16. Bartels M, Geest CR, Bierings M, Buitenhuis M, Coffer PJ. Histone deacetylase inhibition modulates cell fate decisions during myeloid differentiation. Haematologica. 2010;95(7):1052–60.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  17. Blum W, Klisovic RB, Hackanson B, Liu Z, Liu S, Devine H, et al. Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. J Clin Oncol : off J Am Soc Clin Oncol. 2007;25(25):3884–91.

    Article  CAS  Google Scholar 

  18. Kuendgen A, Gattermann N. Valproic acid for the treatment of myeloid malignancies. Cancer. 2007;110(5):943–54.

    Article  PubMed  CAS  Google Scholar 

  19. Kuendgen A, Knipp S, Fox F, Strupp C, Hildebrandt B, Steidl C, et al. Results of a phase 2 study of valproic acid alone or in combination with all-trans retinoic acid in 75 patients with myelodysplastic syndrome and relapsed or refractory acute myeloid leukemia. Ann Hematol. 2005;84 Suppl 1:61–6.

    Article  PubMed  CAS  Google Scholar 

  20. Morotti A, Cilloni D, Messa F, Arruga F, Defilippi I, Carturan S, et al. Valproate enhances imatinib-induced growth arrest and apoptosis in chronic myeloid leukemia cells. Cancer. 2006;106(5):1188–96.

    Article  PubMed  CAS  Google Scholar 

  21. Federico M, Bagella L. Histone Deacetylase Inhibitors in the Treatment of Hematological Malignancies and Solid Tumors. J Biomed Biotechnol. 2011;2011

  22. Bouzar AB, Boxus M, Defoiche J, Berchem G, Macallan D, Pettengell R, et al. Valproate synergizes with purine nucleoside analogues to induce apoptosis of B-chronic lymphocytic leukaemia cells. Br J Haematol. 2009;144(1):41–52.

    Article  PubMed  CAS  Google Scholar 

  23. Finkel T, Deng CX, Mostoslavsky R. Recent progress in the biology and physiology of sirtuins. Nature. 2009;460(7255):587–91.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  24. Galli M, Van Gool F, Rongvaux A, Andris F, Leo O. The nicotinamide phosphoribosyltransferase: a molecular link between metabolism, inflammation, and cancer. Cancer Res. 2010;70(1):8–11.

    Article  PubMed  CAS  Google Scholar 

  25. Byles V, Zhu L, Lovaas JD, Chmilewski LK, Wang J, Faller DV, et al. SIRT1 induces EMT by cooperating with EMT transcription factors and enhances prostate cancer cell migration and metastasis. Oncogene. 2012;31(43):4619–29.

    Article  PubMed  CAS  Google Scholar 

  26. Cea M, Cagnetta A, Gobbi M, Patrone F, Richardson PG, Hideshima T, et al. New insights into the treatment of multiple myeloma with histone deacetylase inhibitors. Curr Pharm Des. 2013;19(4):734–44.

    Article  PubMed  CAS  Google Scholar 

  27. Rezaei PF, Fouladdel S, Hassani S, Yousefbeyk F, Ghaffari SM, Amin G, et al. Induction of apoptosis and cell cycle arrest by pericarp polyphenol-rich extract of Baneh in human colon carcinoma HT29 cells. Food Chem toxicol : Int J publ Br Ind Biol Res Assoc. 2012;50(3–4):1054–9.

    Article  CAS  Google Scholar 

  28. Hafizi M, Bakhshandeh B, Soleimani M, Atashi A. Exploring the enkephalinergic differentiation potential in adult stem cells for cell therapy and drug screening implications. In vitro cellular & developmental biology – Animal. 2012;48(9):562–9.

    Article  CAS  Google Scholar 

  29. Zhang Y, Yu G, Wang D, Hu Y, Lei W. ERK1/2 activation plays important roles in the opposite effects of Trichostatin A in non-cancer and cancer cells. Toxicon : Off J Int Soc Toxinol. 2011;57(6):932–7.

    Article  CAS  Google Scholar 

  30. Azad N, Zahnow CA, Rudin CM, Baylin SB. The future of epigenetic therapy in solid tumours—lessons from the past. Nat Rev Clin Oncol. 2013;10(5):256–66.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  31. Adwan L, Zawia NH. Epigenetics: a novel therapeutic approach for the treatment of Alzheimer’s disease. Pharmacol Ther. 2013;139(1):41–50.

    Article  PubMed  CAS  Google Scholar 

  32. Koutsounas I, Giaginis C, Patsouris E, Theocharis S. Current evidence for histone deacetylase inhibitors in pancreatic cancer. World J Gastroenterol : WJG. 2013;19(6):813–28.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  33. Byler TK, Leocadio D, Shapiro O, Bratslavsky G, Stodgell CJ, Wood RW, et al. Valproic acid decreases urothelial cancer cell proliferation and induces thrombospondin-1 expression. BMC Urol. 2012;12:21.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  34. Cho YK, Eom GH, Kee HJ, Kim HS, Choi WY, Nam KI, et al. Sodium valproate, a histone deacetylase inhibitor, but not captopril, prevents right ventricular hypertrophy in rats. Circ J : Off J Jap Circ Soc. 2010;74(4):760–70.

    Article  CAS  Google Scholar 

  35. Ververis K, Hiong A, Karagiannis TC, Licciardi PV. Histone deacetylase inhibitors (HDACIs): multitargeted anticancer agents. Biol: Targets Ther. 2013;7:47–60.

    CAS  Google Scholar 

  36. Koutsounas I, Giaginis C, Theocharis S. Histone deacetylase inhibitors and pancreatic cancer: are there any promising clinical trials? World J Gastroenterol : WJG. 2013;19(8):1173–81.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  37. Hrebackova J, Hrabeta J, Eckschlager T. Valproic acid in the complex therapy of malignant tumors. Curr Drug Targets. 2010;11(3):361–79.

    Article  PubMed  CAS  Google Scholar 

  38. Cea M, Soncini D, Fruscione F, Raffaghello L, Garuti A, Emionite L, et al. Synergistic interactions between HDAC and sirtuin inhibitors in human leukemia cells. PLoS ONE. 2011;6(7):e22739.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to acknowledge the financial support of the Research Council of the University of Tehran and the Stem Cell Technology Research Center.

Author information

Authors and Affiliations

  1. Department of Biochemistry, Institute of Biochemistry and Biophysics, University of Tehran, P.O. Box 13145-1384, Tehran, Iran

    Hanieh Jafary & Shahin Ahmadian

  2. Department of Hematology, Faculty of Medical Science, Tarbiat Modares University, P.O. Box 14115-111, Tehran, Iran

    Masoud Soleimani

  3. Department of Stem Cell Biology, Stem Cell Technology Research Center, Tehran, Iran

    Masoud Soleimani

Authors
  1. Hanieh Jafary
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shahin Ahmadian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masoud Soleimani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Shahin Ahmadian or Masoud Soleimani.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jafary, H., Ahmadian, S. & Soleimani, M. The enhanced apoptosis and antiproliferative response to combined treatment with valproate and nicotinamide in MCF-7 breast cancer cells. Tumor Biol. 35, 2701–2710 (2014). https://doi.org/10.1007/s13277-013-1356-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-013-1356-0

Keywords

Search

Navigation