Skip to main content

Synergistic suppressive effect of PARP-1 inhibitor PJ34 and HDAC inhibitor SAHA on proliferation of liver cancer cells

Journal of Huazhong University of Science and Technology [Medical Sciences] volume 35, pages 535–540 (2015)Cite this article

Summary

Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors and histone deacetylase (HDAC) inhibitors have recently emerged as promising anticancer drugs. The aim of this study was to investigate the effect of combination treatment with the PARP inhibitor PJ34 and HDAC inhibitor SAHA on the proliferation of liver cancer cells. Cell proliferation and apoptosis were assessed in three human liver cancer cell lines (HepG2, Hep3B and HCC-LM3) treated with PJ34 (8 μmol/L) and SAHA (1 μmol/L), alone or combined, by Cell Counting Kit-8 assay and flow cytometry, respectively. The nude mice bearing subcutaneous HepG2 tumors were administered different groups of drugs (10 mg/kg PJ34, 25 mg/kg SAHA, 10 mg/kg PJ34+25 mg/kg SAHA), and the inhibition rates of tumor growth were compared between groups. The results showed that combined use of PJ34 and SAHA could synergistically inhibit the proliferation of liver cancer cell lines HepG2, Hep3B and HCC-LM3. The apoptosis rate of HepG2 cells treated with PJ34+SAHA was significantly higher than that of HepG2 cells treated with PJ34 or SAHA alone (P<0.05). In vivo, the tumor inhibition rates were 53.5%, 61.4% and 82.6% in PJ34, SAHA and PJ34+SAHA groups, respectively. The combined use of PJ34 and SAHA could significantly inhibit the xenograft tumor growth when compared with use of PJ34 or SAHA alone (P<0.05). It was led to conclude that PJ34 and SAHA can synergistically suppress the proliferation of liver cancer cells.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

References

  1. Lafaro KJ, Demirjian AN, Pawlik TM. Epidemiology of hepatocellular carcinoma. Surg Oncol Clin N Am, 2015,24(1):1–17

    PubMed  Article  Google Scholar 

  2. Bruix J, Gores GJ, Mazzaferro V. Hepatocellular carcinoma: clinical frontiers and perspectives. Gut, 2014,63(5):844–855

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  3. Ma L, Chua MS, Andrisani O, et al. Epigenetics in hepatocellular carcinoma: an update and future therapy perspectives. World J Gastroenterol, 2014,20(2):333–345

    PubMed Central  PubMed  Article  Google Scholar 

  4. Yang SF, Chang CW, Wei RJ, et al. Involvement of DNA damage response pathways in hepatocellular carcinoma. Biomed Res Int, 2014,2014:153867

    PubMed Central  PubMed  Google Scholar 

  5. Beck C, Robert I, Reina-San-Martin B, et al. Poly(ADP-ribose) polymerases in double-strand break repair: Focus on PARP1, PARP2 and PARP3. Exp Cell Res, 2014,329(1):18–25

    CAS  PubMed  Article  Google Scholar 

  6. McCabe N, Turner NC, Lord CJ, et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res, 2006,66(16):8109–8115

    CAS  PubMed  Article  Google Scholar 

  7. Bast RC Jr, Mills GB. Personalizing therapy for ovarian cancer: BRCAness and beyond. J Clin Oncol, 2010,28(22):3545–3548

    CAS  PubMed  Article  Google Scholar 

  8. De Summa S, Pinto R, Sambiasi D, et al. BRCAness: a deeper insight into basal-like breast tumors. Ann Oncol, 2013,24(8):13–21

    Google Scholar 

  9. Robert T, Vanoli F, Chiolo I, et al. HDACs link the DNA damage response, processing of double-strand breaks and autophagy. Nature, 2011,471(7336):74–79

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  10. Lahue RS, Frizzell A. Histone deacetylase complexes as caretakers of genome stability. Epigenetics, 2012,7(8):806–810

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  11. Clamp A, Jayson G. PARP inhibitors in BRCA mutation-associated ovarian cancer. Lancet Oncol, 2015,16(1):10–12

    CAS  PubMed  Article  Google Scholar 

  12. Huang SH, Xiong M, Chen XP, et al. PJ34, an inhibitor of PARP-1, suppresses cell growth and enhances the suppressive effects of cisplatin in liver cancer cells. Oncol Rep, 2008,20(3):567–572

    CAS  PubMed  Google Scholar 

  13. Nogami Y, Banno K, Kisu I, et al. Current status of molecular-targeted drugs for endometrial cancer. Mol Clin Oncol, 2013,1(5):799–804

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Gourzones-Dmitriev C, Kassambara A, Sahota S, et al. DNA repair pathways in human multiple myeloma: role in oncogenesis and potential targets for treatment. Cell Cycle, 2013,12(17):2760–2773

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  15. Bose P, Dai Y, Grant S. Histone deacetylase inhibitor (HDACI) mechanisms of action: emerging insights. Pharmacol Ther, 2014,143(3):323–336

    CAS  PubMed  Article  Google Scholar 

  16. Garcia-Manero G, Yang H, Bueso-Ramos C, et al. Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. Blood, 2008,111(3):1060–1066

    CAS  PubMed  Article  Google Scholar 

  17. Lee JH, Choy ML, Ngo L, et al. Histone deacetylase inhibitor induces DNA damage, which normal but not transformed cells can repair. Proc Natl Acad Sci USA, 2010,107(33):14639–14644

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  18. Alli E, Solow-Cordero D, Casey SC, et al. Therapeutic targeting of BRCA1-mutated breast cancers with agents that activate DNA repair. Cancer Res, 2014,74(21):6205–6215

    CAS  PubMed  Article  Google Scholar 

  19. Pothuri B. BRCA1- and BRCA2-related mutations: therapeutic implications in ovarian cancer. Ann Oncol, 2013,24(8):22–27

    Google Scholar 

  20. Duvic M, Talpur R, Ni X, et al. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood, 2007,109(1):31–39

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  21. Zhou C, Ji J, Shi M, et al. Suberoylanilide hydroxamic acid enhances the antitumor activity of oxaliplatin by reversing the oxaliplatininduced Src activation in gastric cancer cells. Mol Med Rep, 2014,10(5):2729–2735

    CAS  PubMed  Google Scholar 

  22. Xiao W, Graham PH, Hao J, et al. Combination therapy with the histone deacetylase inhibitor LBH589 and radiation is an effective regimen for prostate cancer cells. PLoS One, 2013,8(8):74253

    Article  Google Scholar 

  23. Adimoolam S, Sirisawad M, Chen J, et al. HDAC inhibitor PCI-24781 decreases RAD51 expression and inhibits homologous recombination. Proc Natl Acad Sci USA, 2007,104(49):19482–19487

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  24. Li X, Chen BD. Histone deacetylase inhibitor M344 inhibits cell proliferation and induces apoptosis in human THP-1 leukemia cells. Am J Biomed Sci, 2009,1(4):352–363

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  25. Petruccelli LA, Pettersson F, Del Rincon SV, et al. Expression of leukemia-associated fusion proteins increases sensitivity to histone deacetylase inhibitorinduced DNA damage and apoptosis. Mol Cancer Ther, 2013,12(8):1591–1604

    CAS  PubMed  Article  Google Scholar 

Download references

Author information

Affiliations

  1. Research Laboratory and Hepatic Surgery Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Bin-yong Liang, Gui-bao Ji, Er-lei Zhang, Zun-yi Zhang, Ke-shuai Dong, Xiao-ping Chen & Zhi-yong Huang

  2. Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Min Xiong

  3. Department of General Surgery, Pu’ai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Gui-bao Ji

Authors
  1. Bin-yong Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Min Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gui-bao Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Er-lei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zun-yi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ke-shuai Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiao-ping Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zhi-yong Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhi-yong Huang.

Additional information

This project was supported by grants from the National Natural Science Foundation of China (No. 81172293) and the New Century Excellent Talent Foundation of Ministry of Education of China (No. NCET-04-0701).

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Liang, By., Xiong, M., Ji, Gb. et al. Synergistic suppressive effect of PARP-1 inhibitor PJ34 and HDAC inhibitor SAHA on proliferation of liver cancer cells. J. Huazhong Univ. Sci. Technol. [Med. Sci.] 35, 535–540 (2015). https://doi.org/10.1007/s11596-015-1466-6

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11596-015-1466-6

Key words

  • poly (ADP-ribose) polymerase-1
  • PJ34
  • histone deacetylase
  • SAHA
  • liver cancer
  • proliferation