DOI QR코드

DOI QR Code

Antitumor Activity of Histone Deacetylase Inhibitor Trichostatin A in Osteosarcoma Cells

  • Cheng, Dong-Dong (Department of Orthopeadics, the Sixth People's Hospital, Shanghai JiaoTong University) ;
  • Yang, Qing-Cheng (Department of Orthopeadics, the Sixth People's Hospital, Shanghai JiaoTong University) ;
  • Zhang, Zhi-Chang (Department of Orthopeadics, the Sixth People's Hospital, Shanghai JiaoTong University) ;
  • Yang, Cui-Xia (Laboratory Center, the Sixth People's Hospital, Shanghai JiaoTong University) ;
  • Liu, Yi-Wen (Laboratory Center, the Sixth People's Hospital, Shanghai JiaoTong University)
  • Published : 2012.04.30

Abstract

Background: Histone deacetylase (HDAC) inhibitors have been reported to induce cell growth arrest, apoptosis and differentiation of tumor cells. The present study aimed to examine the effects of trichostatin A (TSA), one such inhibitor, on the cell cycle, apoptosis and invasiveness of osteosarcoma cells. Methods: MG-63 cells were treated with TSA at various concentrations. Then, cell growth and apoptosis were determined by 3-(4, 5-dimethyl-2-thiazolyl)-2H-tetrazolium bromide (MTT) and TUNEL assays, respectively; cell cycling was assessed by flow cytometry; invasion assays were performed with the transwell Boyden Chamber system. Results: MTT assays revealed that TSA significantly inhibited the growth of MG-63 cells in a concentration and time dependent manner. TSA treated cells demonstrated morphological changes indicative of apoptosis and TUNEL assays revealed increased apoptosis of MG-63 cells after TSA treatment. Flow cytometry showed that TSA arrested the cell cycle in G1/G2 phase and annexin V positive apoptotic cells increased markedly. In addition, the invasiveness of MG-63 cells was inhibited by TSA in a concentration dependent manner. Conclusion: Our findings demonstrate that TSA inhibits the proliferation, induces apoptosis and inhibits invasiveness of osteosarcoma cells in vitro. HDAC inhibitors may thus have promise to become new therapeutic agents against osteosarcoma.

Keywords

References

  1. Aquerreta I, Aldaz A, Giraldez J, Sierrasesumaga L (2004). Methotrexate pharmacokinetics and survival in osteosarcoma. Pediatr Blood Cancer, 42, 52-8. https://doi.org/10.1002/pbc.10443
  2. Chiba T, Yokosuka O, Fukai K, et al (2004). Cell growth inhibition and gene expression induced by the histone deacetylase inhibitor, trichostatin A, on human hepatoma cells. Oncology, 66, 481-91. https://doi.org/10.1159/000079503
  3. Donadelli M, Costanzo C, Faggioli L, et al (2003). Trichostatin A, an inhibitor of histone deacetylases, strongly suppresses growth of pancreatic adenocarcinoma cells. Mol Carcinog, 38, 59-69. https://doi.org/10.1002/mc.10145
  4. Finnin MS, Donigian JR, Cohen A, et al (1999). Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature, 401, 188-93. https://doi.org/10.1038/43710
  5. Ghizzoni M, Haisma HJ, Maarsingh H, Dekker FJ (2011). Histone acetyltransferases are crucial regulators in NF-${\kappa}B$ mediated inflammation. Drug Discov Today, 16, 504-11. https://doi.org/10.1016/j.drudis.2011.03.009
  6. Hirose T, Sowa Y, Takahashi S, et al (2003). p53-independent induction of Gadd45 by histone deacetylase inhibitor: coordinate regulation by transcription factors Oct-1 and NF-Y. Oncogene, 22, 7762-73. https://doi.org/10.1038/sj.onc.1207091
  7. Kim MS, Kwon HJ, Lee YM, et al (2001). Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat Med, 7, 437-43. https://doi.org/10.1038/86507
  8. Kim Y, Park H, Lim Y, et al (2003). Decreased syndecan-2 expression correlates with trichostatin-A inducedmorphological changes and reduced tumorigenic activity in colon carcinoma cells. Oncogene, 22, 826-30. https://doi.org/10.1038/sj.onc.1206068
  9. Li MH, Miao ZH, Tan WF, et al (2004). Pseudolaric acid B inhibits angiogenesis and reduces hypoxia-inducible factor 1alpha by promoting proteasome-mediated degradation. Clin Cancer Res, 10, 8266-74. https://doi.org/10.1158/1078-0432.CCR-04-0951
  10. Liu LT, Chang HC, Chiang LC, Hung WC (2003). Histone deacetylase inhibitor up-regulates RECK to inhibit MMP-2 activation and cancer cell invasion. Cancer Res, 63, 3069-72.
  11. Loidl P, Grobner P (1987). Postsynthetic acetylation of histones during the cell cycle: a general function for the displacement of histones during chromatin rearrangements. Nucleic Acids Res, 15, 8351-66. https://doi.org/10.1093/nar/15.20.8351
  12. Marks PA, Richon VM, Breslow R, Rifkind RA (2001). Histone deacetylase inhibitors as new cancer drugs. Curr Opin Oncol, 13, 477-83. https://doi.org/10.1097/00001622-200111000-00010
  13. Mosmann T (1983). Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods, 65, 55-63. https://doi.org/10.1016/0022-1759(83)90303-4
  14. Muller M, Strand S, Hug H, et al (1997). Drug-induced apoptosis in hepatoma cells is mediated by the CD95 (APO-1/Fas) receptor/ligand system and involves activation of wild-type p53. J Clin Invest, 99, 403-13. https://doi.org/10.1172/JCI119174
  15. Sowa Y, Orita T, Minamikawa S, et al (1997). Histone deacetylase inhibitor activates the WAF1/Cip1 gene promoter through the Sp1 sites. Biochem Biophys Res Commun, 241, 142-50. https://doi.org/10.1006/bbrc.1997.7786
  16. Strait KA, Dabbas B, Hammond EH,et al (2002). Cell cycle blockade and differentiation of ovarian cancer cells by the histone deacetylase inhibitor trichostatin A are associated with changes in p21, Rb, and Id proteins. Mol Cancer Ther, 1, 1181-90.
  17. Vigushin DM, Ali S, Pace PE, et al (2001). Trichostatin A is a histone deacetylase inhibitor with potent antitumor activity against breast cancer in vivo. Clin Cancer Res, 7, 971-6.
  18. Williams RJ (2001). Trichostatin A, an inhibitor of histone deacetylase, inhibits hypoxia-induced angiogenesis. Expert Opin Investig Drugs, 10, 1571-3. https://doi.org/10.1517/13543784.10.8.1571
  19. Wolffe AP, Guschin D (2000). Review: chromatin structural features and targets that regulate transcription. J Struct Biol, 129, 102-22. https://doi.org/10.1006/jsbi.2000.4217
  20. Yoshida M, Horinouchi S, Beppu T (1995). Trichostatin A and trapoxin: novel chemical probes for the role of histone acetylation in chromatin structure and function. Bioessays, 17, 423-30. https://doi.org/10.1002/bies.950170510

Cited by

  1. Histone Deacetylase Inhibitor Trichostatin A Enhances Antitumor Effects of Docetaxel or Erlotinib in A549 Cell Line vol.13, pp.7, 2012, https://doi.org/10.7314/APJCP.2012.13.7.3471
  2. Sustained Low-Dose Treatment with the Histone Deacetylase Inhibitor LBH589 Induces Terminal Differentiation of Osteosarcoma Cells vol.2013, pp.1369-1643, 2013, https://doi.org/10.1155/2013/608964
  3. Trichostatin A-induced Apoptosis is Mediated by Krüppel-like Factor 4 in Ovarian and Lung Cancer vol.15, pp.16, 2014, https://doi.org/10.7314/APJCP.2014.15.16.6581
  4. A New Cell Counting Method to Evaluate Anti-tumor Compound Activity vol.15, pp.8, 2014, https://doi.org/10.7314/APJCP.2014.15.8.3397
  5. TRPM2 Mediates Histone Deacetylase Inhibition-Induced Apoptosis in Bladder Cancer Cells vol.30, pp.2, 2015, https://doi.org/10.1089/cbr.2014.1697
  6. Effects of histone deacetylase inhibitor trichostatin A combined with cisplatin on apoptosis of A549 cell line vol.6, pp.2, 2015, https://doi.org/10.1111/1759-7714.12167
  7. Histone deacetylase inhibitors induce invasion of human melanoma cells in vitro via differential regulation of N-cadherin expression and RhoA activity vol.16, pp.1, 2016, https://doi.org/10.1186/s12885-016-2693-3
  8. Metformin Synergistically Enhances Antitumor Activity of Histone Deacetylase Inhibitor Trichostatin A Against Osteosarcoma Cell Line vol.32, pp.4, 2013, https://doi.org/10.1089/dna.2012.1926
  9. HDAC2-mediated upregulation of IL-6 triggers the migration of osteosarcoma cells pp.1573-6822, 2019, https://doi.org/10.1007/s10565-019-09459-7