Skip to main content

Advertisement

SpringerLink
Log in

Combinatory effects of vaccinia virus VG9 and the STAT3 inhibitor Stattic on cancer therapy

  • Original Article
  • Published:
Archives of Virology Aims and scope Submit manuscript

Abstract

The recombinant vaccinia virus VG9 and the STAT3 inhibitor Stattic were combined to kill cancer cells via both oncolytic activity and inhibition of STAT3 phosphorylation in cells. The combinatory anti-tumour activity of these compounds was superior to the activity of VG9 or Stattic alone in vivo. The inhibition of tumour growth occurred via increased apoptosis and autophagy pathways. Furthermore, the combinatory anti-tumour activity was more efficient than that of VG9 or Stattic alone on xenografts, especially in nude mice.

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

Similar content being viewed by others

References

  1. Heise C, Sampson-Johannes A, Williams A, McCormick F, Von Hoff DD, Kirn DH (1997) ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents. Nat Med 3:639–645

    Article  CAS  PubMed  Google Scholar 

  2. Walker JR, McGeagh KG, Sundaresan P, Jorgensen TJ, Rabkin SD, Martuza RL (1999) Local and systemic therapy of human prostate adenocarcinoma with the conditionally replicating herpes simplex virus vector G207. Hum Gene Ther 10:2237–2243

    Article  CAS  PubMed  Google Scholar 

  3. Phuangsab A, Lorence RM, Reichard KW, Peeples ME, Walter RJ (2001) Newcastle disease virus therapy of human tumor xenografts: antitumor effects of local or systemic administration. Cancer Lett 172:27–36

    Article  CAS  PubMed  Google Scholar 

  4. Puhlmann M, Gnant M, Brown CK, Alexander HR, Bartlett DL (1999) Thymidine kinase-deleted vaccinia virus expressing purine nucleoside phosphorylase as a vector for tumor-directed gene therapy. Hum Gene Ther 10:649–657

    Article  CAS  PubMed  Google Scholar 

  5. Thorne SH, Hermiston T, Kirn D (2005) Oncolytic virotherapy: approaches to tumor targeting and enhancing antitumor effects. Semin Oncol 32:537–548

    Article  CAS  PubMed  Google Scholar 

  6. Everts B, van der Poel HG (2005) Replication-selective oncolytic viruses in the treatment of cancer. Cancer Gene Ther 12:141–161

    Article  CAS  PubMed  Google Scholar 

  7. Kirn DH, McCormick F (1996) Replicating viruses as selective cancer therapeutics. Mol Med Today 2:519–527

    Article  CAS  PubMed  Google Scholar 

  8. McAneny D, Ryan CA, Beazley RM, Kaufman HL (1996) Results of a phase I trial of a recombinant vaccinia virus that expresses carcinoembryonic antigen in patients with advanced colorectal cancer. Ann Surg Oncol 3:495–500

    Article  CAS  PubMed  Google Scholar 

  9. Peplinski GR, Tsung K, Meko JB, Norton JA (1995) In vivo gene therapy of a murine pancreas tumor with recombinant vaccinia virus encoding human interleukin-1beta. Surgery 118:185–190 (discussion 190–181)

    Article  CAS  PubMed  Google Scholar 

  10. Thorne SH, Hwang TH, O’Gorman WE et al (2007) Rational strain selection and engineering creates a broad-spectrum, systemically effective oncolytic poxvirus, JX-963. J Clin Invest 117:3350–3358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Park BH, Hwang T, Liu TC et al (2008) Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial. Lancet Oncol 9:533–542

    Article  CAS  PubMed  Google Scholar 

  12. Liu TC, Hwang T, Park BH, Bell J, Kirn DH (2008) The targeted oncolytic poxvirus JX-594 demonstrates antitumoral, antivascular, and anti-HBV activities in patients with hepatocellular carcinoma. Mol Ther 16:1637–1642

    Article  CAS  PubMed  Google Scholar 

  13. Zhu R, Liu Q, Huang W, Yu Y, Wang Y (2014) Comparison of the replication characteristics of vaccinia virus strains Guang 9 and Tian Tan in vivo and in vitro. Arch Virol 159:2587–2596

    Article  CAS  PubMed  Google Scholar 

  14. Deng L, Fan J, Guo M, Huang B (2016) Oncolytic and immunologic cancer therapy with GM-CSF-armed vaccinia virus of Tian Tan strain Guang9. Cancer Lett 372(2):251–257

    Article  CAS  PubMed  Google Scholar 

  15. Yu H, Lee H, Herrman A, Buettner R, Jove R (2014) Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer 14(11):736–746

    Article  CAS  PubMed  Google Scholar 

  16. Sriuranpong V, Park JI, Amornphimoltham P et al (2003) Epidermal growth factor receptor- independent constitutive activation of STAT3 in head and neck squamous cell carcinoma is mediated by the autocrine/paracrine stimulation of the interleukin 6/gp130 cytokine system. Cancer Res 63(11):2948–2956

    CAS  PubMed  Google Scholar 

  17. Bromberg JF, Wrzeszczynska MH, Devgan G et al (1999) Stat3 as an oncogene. Cell 98(3):295–303

    Article  CAS  Google Scholar 

  18. Hsieh FC, Cheng G, Lin J (2005) Evaluation of potential Stat3-regulated genes in human breast cancer. Biochem Biophys Res Commun 35(2):292–299

    Article  CAS  Google Scholar 

  19. Punjabi AS, Carroll PA, Chen L, Lagunoff M (2007) Persistent activation of STAT3 by latent Kaposi’s sarcoma-associated herpesvirus infection of endothelial cells. J Virol 81(5):2449–2458

    Article  CAS  PubMed  Google Scholar 

  20. Muromoto R, Ikeda O, Okabe K, Togi S, Kamitani S, Fujimuro M, Harada S, Oritani K, Matsuda T (2009) Epstein–Barr virus-derived EBNA2 regulates STAT3 activation. Biochem Biophys Res Commun 378(3):439–443

    Article  CAS  PubMed  Google Scholar 

  21. Lee YH, Yun YJ (1998) HBx protein of hepatitis B virus activates Jak1-STAT signaling. Biol Chem 273(39):25510–25515

    Article  CAS  Google Scholar 

  22. Schust J, Sperl B, Hollis A, Mayer TU, Berg T (2006) Stattic: a small molecule inhibitor of STAT3 activation and dimerization. Chem Biol 13:1235–1242

    Article  CAS  PubMed  Google Scholar 

  23. Pa Y, Zhou F, Zhang R, Claret FX (2013) Stat3 inhibitor static exhibits potent antitumor activity and induces chemo- and radio-sensitivity in nasopharyngeal carcinoma. PLoS One 8(1):e54565

    Article  CAS  Google Scholar 

  24. Adachi M, Cui C, Dodge CT, Bhayani MK, Lai SY (2012) Targeting STAT3 inhibits growth and enhances radiosensitivity in head and neck squamous cell carcinoma. Oral Oncol 48:1220–1226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhang Q, Zhang C, He J, Guo Q, Hu DS, Yang X, Wang JF, Kang YH, She RF, Wang ZM, Li DF, Huang GH, Ma ZM, Mao WD, Zhou XY, Xiao CY, Sun XC, Ma JX (2015) STAT3 inhibitor stattic enhances radiosensitivity in esophageal squamous cell carcinoma. Tumor Biol 36:2135–2142

    Article  CAS  Google Scholar 

  26. Deng LL, Fan J, Ding YD, Zhang J, Zhou B, Zhang Y, Huang B (2017) Oncolytic efficacy of thymidine kinase-deleted vaccinia virus strain Guang9. Oncotarget 8:40533–40543

    PubMed  PubMed Central  Google Scholar 

  27. Bliss CI (1939) The toxicity of poisons applied jointly. Ann Appl Biol 26:585–615

    Article  CAS  Google Scholar 

  28. Huang H, Liu S, Jean M, Simpson S, Huang H, Merkley M, Hayashi T, Kong W, Rodríguez-Sánchez I, Zhang X, Yosief HO, Miao H, Que J, Kobie JJ, Bradner J, Santoso NG, Zhang W, Zhu J (2017) A novel bromodomain inhibitor reverses hiv-1 latency through specific binding with brd4 to promote tat and p-tefb association. Front Microbiol 8:1035

    Article  PubMed  PubMed Central  Google Scholar 

  29. Hwang TH, Moon A, Burke J et al (2011) A mechanistic proof-of-concept clinical trial with JX-594, a targeted multi-mechanistic oncolytic poxvirus, in patients with metastatic melanoma. Mol Ther 19:1913–1922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Heo J, Reid T, Ruo L et al (2013) Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat Med 19:329–336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Foloppe J, Kintz J, Futin N et al (2008) Targeted delivery of a suicide gene to human colorectal tumors by a conditionally replicating vaccinia virus. Gene Ther 15:1361–1371

    Article  CAS  PubMed  Google Scholar 

  32. Zhang Q, Yu YA, Wang E et al (2007) Eradication of solid human breast tumors in nude mice with an intravenously injected light-emitting oncolytic vaccinia virus. Cancer Res 67:10038–10046

    Article  CAS  PubMed  Google Scholar 

  33. Buller RM, Smith GL, Cremer K, Notkins AL, Moss B (1985) Decreased virulence of recombinant vaccinia virus expression vectors is associated with a thymidine kinase-negative phenotype. Nature 317:813–815

    Article  CAS  Google Scholar 

  34. Gnant MF, Puhlmann M, Bartlett DL, Alexander HR Jr (1999) Regional versus systemic delivery of recombinant vaccinia virus as suicide gene therapy for murine liver metastases. Ann Surg 230:352–360 (discussion 360–351)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. McIlwain DR, Grusdat M, Pozdeev VI, Xu HC, Shinde P, Reardon C, Hao Z, Beyer M, Bergthaler A, Häussinger D, Nolan GP, Lang KS, Lang PA (2015) T-cell STAT3 is required for the maintenance of humora l immunity to LCMV. Eur J Immunol. 45:418–427

    Article  CAS  PubMed  Google Scholar 

  36. Ryerson MR, Richards MM, Kvansakul M, Hawkins CJ, Shisler JL (2017) Vaccinia virus strain Western Reserve encodes a novel inhibitor of apoptosis that associates with the apoptosome. J Virol 91:e01385-17. https://doi.org/10.1128/jvi.01385-17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Nichols DB, De Martini W, Cottrell J (2017) Poxviruses utilize multiple strategies to inhibit apoptosis viruses. Viruses 9:215. https://doi.org/10.3390/v9080215

    Article  CAS  PubMed Central  Google Scholar 

  38. Veyer DL, Carrara G, Maluquer de Motes C, Smith GL (2017) Vaccinia virus evasion of regulated cell death. Immunol Lett 186:68–80

    Article  CAS  PubMed  Google Scholar 

  39. Gubser C, Bergamaschi D, Hollinshead M, Lu X, van Kuppeveld FJ, Smith GL (2007) A new inhibitor of apoptosis from vaccinia virus and eukaryotes. PLoS Pathog 3:e17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Saraiva N, Prole DL, Carrara G, Maluquer de Motes C, Johnson BF, Byrne B, Taylor CW, Smith GL (2013) Human and viral Golgi anti-apoptotic proteins (GAAPs) oligomerize via different mechanisms and monomeric GAAP inhibits apoptosis and modulates calcium. J Biol Chem 288:13057–13067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Chitnis NS, Paul ER, Lawrence PK, Henderson CW, Ganapathy S, Taylor PV, Virdi KS, D’Costa SM, May AR, Bilimoria SL (2011) A virion-associated protein kinase induces apoptosis. J Virol 85:13144–13152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Baixeras E, Cebrián A, Albar JP, Salas J, Martínez-A C, Viñuela E, Revilla Y (1998) Vaccinia virus-induced apoptosis in immature B lymphocytes: role of cellular Bcl-2. Virus Res 58:107–113

    Article  CAS  PubMed  Google Scholar 

  43. Engelmayer J, Larsson M, Subklewe M, Chahroudi A, Cox WI, Steinman RM, Bhardwaj N (1999) Vaccinia virus inhibits the maturation of human dendritic cells: a novel mechanism of immune evasion. J Immunol 163:6762–6768

    CAS  PubMed  Google Scholar 

  44. Ramsey-Ewing A, Moss B (1998) Apoptosis induced by a postbinding step of vaccinia virus entry into Chinese hamster ovary cells. Virology 242:138–149

    Article  CAS  PubMed  Google Scholar 

  45. Guerra S, López-Fernández LA, Pascual-Montano A, Nájera JL, Zaballos A, Esteban M (2006) Host response to the attenuated poxvirus vector NYVAC: upregulation of apoptotic genes and NF-kappaB-responsive genes in infected HeLa cells. J Virol 80:985–998

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Greiner S, Humrich JY, Thuman P, Sauter B, Schuler G, Jenne L (2006) The highly attenuated vaccinia virus strain modified virus Ankara induces apoptosis in melanoma cells and allows bystander dendritic cells to generate a potent anti-tumoral immunity. Clin Exp Immunol 146:344–353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Liskova J, Knitlova J, Honner R, Melkova Z (2011) Apoptosis and necrosis in vaccinia virus-infected HeLa G and BSC-40 cells. Virus Res 160:40–50

    Article  CAS  PubMed  Google Scholar 

  48. Guzman E, Cubillos-Zapata C, Cottingham MG, Gilbert SC, Prentice H, Charleston B, Hope JC (2012) Modified vaccinia virus Ankara-based vaccine vectors induce apoptosis in dendritic cells draining from the skin via both the extrinsic and intrinsic caspase pathways, preventing efficient antigen presentation. J Virol 86:5452–5466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Liu L, Chavan R, Feinberg MB (2008) Dendritic cells are preferentially targeted among hematolymphocytes by Modified Vaccinia Virus Ankara and play a key role in the induction of virus-specific T cell responses in vivo. BMC Immunol. 9:15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Royo S, Sainz B Jr, Hernandez-Jimenez E, Reyburn H, Lopez-Collazo E, Guerra S (2014) Differential induction of apoptosis, interferon signaling, and phagocytosis in macrophages infected with a panel of attenuated and nonattenuated poxviruses. J Virol 88:5511–5523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation (31671035, 51473071, 21504034), by the National Significant New Drugs Creation Program, by the Jiangsu Province Foundation (BK20161137, BE2016632, BK20170204), and also by the Jiangsu Provincial Medical Innovation Team.

Author information

Authors and Affiliations

  1. Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, No. 20, Qianrong Road, Wuxi, 214063, China

    Runlin Yang, Lizhen Wang, Donghui Pan, Yuping Xu, Junjie Yan, Xinyu Wang, Ziyue Dong & Min Yang

  2. The First School of Clinical Medicine, Nanjing Medical University, Nanjing, 210029, China

    Jie Sheng, Qianhuan Huang & Min Yang

  3. School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, 450000, China

    Min Yang

Authors
  1. Runlin Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lizhen Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jie Sheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qianhuan Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Donghui Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuping Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Junjie Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xinyu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ziyue Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Min Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Runlin Yang or Min Yang.

Ethics declarations

Conflict of interest

The authors have declared that no competing interest exists.

Ethical standards

The animal experiments were approved by the Committee for Ethics of Jiangsu Institute of Nuclear Medicine.

Additional information

Handling Editor: William G Dundon.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

705_2019_4257_MOESM1_ESM.jpg

Supplementary material 1: Fig. S1. Expression of GFP in BEL-7402 cells infected with VG9. A–F, infection withVG9 at different MOIs of A 0 PFU/cell; B 0.01 PFU/cell; C 0.05 PFU/cell; D 0.1PFU/cell; E 0.5 PFU/cell; F 1 PFU/cell. Scale bar: 50 μm (JPG 9462 kb)

705_2019_4257_MOESM2_ESM.jpg

Supplementary material 2: Fig. S2. Western blot analysis showing the expression of apoptosis-associated proteins in HeLa cells treated with 2 μM Stattic alone. The ratios of phospho-STAT3 to total STAT3 on day 1 to day 2 decreased. The levels of caspases-3 and -8 both increased from day 2 to day 3. The ratios of Bcl-2 to Bax decreased. Stattic induced apoptosis in HeLa cells. Data are represented as the mean ± SD. *p < 0.05; **p < 0.01; ***p < 0.001 (t-test) (JPG 949 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, R., Wang, L., Sheng, J. et al. Combinatory effects of vaccinia virus VG9 and the STAT3 inhibitor Stattic on cancer therapy. Arch Virol 164, 1805–1814 (2019). https://doi.org/10.1007/s00705-019-04257-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00705-019-04257-2

Search

Navigation