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Oncolytic herpes simplex virus vectors and taxanes synergize to promote killing of prostate cancer cells

Abstract

Genetically engineered oncolytic herpes simplex virus-1 (HSV-1) vectors selectively replicate in tumor cells causing direct killing whereas sparing normal cells. One clinical limitation of using oncolytic HSV vectors is their attenuated growth. We hypothesized that the appropriately chosen chemotherapeutic agent combined with an oncolytic HSV could be an effective means to promote augmented prostate cancer cell killing both in vitro and in vivo. Here we have identified that G47Δ synergizes with the microtubule-stabilizing taxane agents docetaxel and paclitaxel to enhance the in vitro killing of prostate cancer cells. In vivo efficacy studies show that when combined with docetaxel, G47Δ could be reduced at least 10-fold. Immunoblot analysis revealed that docetaxel-induced accumulation of the phospho-specific mitotic markers op18/stathmin or histone-H3 was markedly reduced by G47Δ, which correlated with enhanced apoptosis and required active viral replication. Furthermore, cell-cycle analysis demonstrated that in the presence of G47Δ, the majority of 4N cells arrested in mitosis were MPM-2-negative, indicative of cells exiting mitosis prematurely. These findings suggest that G47Δ may act in part, on mitotically blocked cells to enhance cell death, which may account for the enhanced antitumor efficacy observed in vivo.

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References

  1. Toda T, Martuza RL, Rabkin SD, Johnson PA . Oncolytic herpes simplex virus vector with enhanced MHC class I presentation and tumor cell killing. Proc Natl Acad Sci USA 2001; 98: 6396–6401.

    Article  Google Scholar 

  2. He B, Chou J, Brandimarti R, Mohr I, Gluzman Y, Roizman B . Suppression of the phenotype of gamma(1)34.5- herpes simplex virus 1: failure of activated RNA-dependent protein kinase to shut off protein synthesis is associated with a deletion in the domain of the alpha47 gene. J Virol 1997; 71: 6049–6054.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Cassady KA, Gross M, Roizman B . The second-site mutation in the herpes simplex virus recombinants lacking the gamma134.5 genes precludes shutoff of protein synthesis by blocking the phosphorylation of eIF-2alpha. J Virol 1998; 72: 7005–7011.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Fukuhara H, Martuza RL, Rabkin SD, Ito Y, Toda T . Oncolytic herpes simplex virus vector g47delta in combination with androgen ablation for the treatment of human prostate adenocarcinoma. Clin Cancer Res 2005; 11: 7886–7890.

    Article  CAS  PubMed  Google Scholar 

  5. Varghese S, Newsome JT, Rabkin SD, McGeagh K, Mahoney D, Nielsen P et al. Preclinical safety evaluation of G207, a replication-competent herpes simplex virus type 1, inoculated intraprostatically in mice and nonhuman primates. Hum Gene Ther 2001; 12: 999–1010.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Toda M, Martuza RL, Kojima H, Rabkin SD . In situ cancer vaccination: an IL-12 defective vector/replication-competent herpes simplex virus combination induces local and systemic antitumor activity. J Immunol 1998; 160: 4457–4464.

    CAS  PubMed  Google Scholar 

  8. Varghese S, Rabkin SD, Nielsen PG, Wang W, Martuza RL . Systemic oncolytic herpes virus therapy of poorly immunogenic prostate cancer metastatic to lung. Clin Cancer Res 2006; 12: 2919–2927.

    Article  CAS  PubMed  Google Scholar 

  9. Varghese S, Rabkin SD, Liu R, Nielsen PG, Ipe T, Martuza RL . Enhanced therapeutic efficacy of IL-12, but not GM-CSF, expressing oncolytic herpes simplex virus for transgenic mouse derived prostate cancers. Cancer Gene Ther 2006; 13: 253–265.

    Article  CAS  PubMed  Google Scholar 

  10. Wilson L, Jordan M . Microtubules as a target for anticancer drugs. Nat Rev Cancer 2004; 4: 253–265.

    Article  PubMed  Google Scholar 

  11. Chen JG, Horwitz SB . Differential mitotic responses to microtubule-stabilizing and—destabilizing drugs. Cancer Res 2002; 62: 1935–1938.

    CAS  PubMed  Google Scholar 

  12. Chen JG, Hang Yang C-P, Cammer M, Horwitz SB . Gene expression and mitotic exit induced by microtubule-stabilizing drugs. Cancer Res 2003; 63: 7891–7899.

    CAS  PubMed  Google Scholar 

  13. Castedo M, Perfettini JL, Roumier T, Andreau K, Medema R, Kroemer G . Cell death by mitotic catastrophe: A molecular definition. Oncogene 2004; 23: 2825–2837.

    Article  CAS  PubMed  Google Scholar 

  14. Ehmann GL, McLean TI, Bachenheimer SL . Herpes simplex virus type 1 infection imposes a G1/S block in asynchronously growing cells and prevents G1 entry in quiescent cells. Virology 2000; 267: 335–349.

    Article  CAS  PubMed  Google Scholar 

  15. Olgiate J, Ehmann GL, Vidyarthi S, Hilton MJ, Bachenheimer SL . Herpes simplex virus induces intracellular redistribution of E2F4 and accumulation of E2F pocket protein complexes. Virology 1999; 258: 257–270.

    Article  CAS  PubMed  Google Scholar 

  16. Song BY, Yeh K-C, Liu J, Knipe DM . Herpes simplex virus gene products required for viral inhibition of expression of G1-phase functions. Virology 2001; 290: 320–328.

    Article  CAS  PubMed  Google Scholar 

  17. Mineta T, Rabkin SD, Yazaki T, Hunter WD, Martuza RL . Attenuated multi-mutated herpes simplex virus-1 for the treatment of malignant gliomas. Nat Med 1995; 1: 938–943.

    Article  CAS  PubMed  Google Scholar 

  18. Chou TC, Talalay P . Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 1984; 22: 27–55.

    CAS  PubMed  Google Scholar 

  19. Motwani M, Xiao-kui L, Schwartz GK . Flavopiridol, a cyclin-dependent kinase inhibitor, prevents spindle inhibitor-induced endoreduplication in human cancer cells. Clin Cancer Res 2000; 6: 924–932.

    CAS  PubMed  Google Scholar 

  20. Yu D-C, Chen Y, Dilley J, Li Y, Embry M, Zhang H et al. Antitumor synergy of CV787, a prostate cancer-specific andenovirus, and paclitaxel and docetaxel. Cancer Res 2001; 61: 517–525.

    CAS  PubMed  Google Scholar 

  21. Chou J, Chen JJ, Gross M, Roizman B . Association of a M(r) 90 000 phosphoprotein with protein kinase PKR in cells exhibiting enhanced phosphorylation of translation initiation factor eIF-2 alpha and premature shutoff of protein synthesis after infection with gamma 134.5- mutants of herpes simplex virus 1. Proc Natl Acad Sci USA 1995; 98: 6396–6401.

    Google Scholar 

  22. Post DE, Fulci G, Chiocca EA, Van Meir EG . Replicative oncolytic herpes simplex viruses in combination cancer therapies. Curr Gene Ther 2004; 4: 41–51.

    Article  CAS  PubMed  Google Scholar 

  23. Petrowsky H, Roberts G, Kooby DA, Burt BM, Bennett JJ, Delman KA et al. Functional interaction between fluorodeoxyuridine-induced cellular alterations and replication of a ribonucleotide reductase-negative herpes simplex virus. J Virol 2001; 75: 7050–7108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Aghi M, Rabkin S, Martuza RL . Effect of chemotherapy-induced DNA repair on oncolytic herpes simplex viral replication. J Natl Cancer Inst 2006; 98: 38–50.

    Article  CAS  PubMed  Google Scholar 

  25. Eisenberg DP, Adusumilli PS, Hendershott KJ, Yu Z, Mullerad M, Chan MK et al. 5-fluorouracil and gemcitabine potentiate the efficacy of oncolytic herpes viral gene therapy in the treatment of pancreatic cancer. J Gastrointest Surg 2005; 9: 1068–1077.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Liu TC, Wakimoto H, Martuza RL, Rabkin SD . Herpes simplex virus Us3(−) mutant as oncolytic strategy and synergizes with phosphatidylinositol 3-kinase-Akt targeting molecular therapeutics. Clin Cancer Res 2007; 13: 5897–5902.

    Article  CAS  PubMed  Google Scholar 

  27. Maiato H, Rieder CL . Stuck in division or passing through: What happens when cells cannot satisfy the spindle assembly checkpoint. Dev Cell 2004; 7: 637–651.

    Article  PubMed  Google Scholar 

  28. Motwani M, Delohery TM, Schwartz GK . Sequential dependent enhancement of caspase activation and apoptosis by flavopiridol on paclitaxel-treated human gastric and breast cancer cells. Clin Cancer Res 1999; 5: 1876–1883.

    CAS  PubMed  Google Scholar 

  29. Wittman S, Bali P, Donapaty S, Nimmanapalli R, Guo F, Yamaguchi H et al. Favopiridol down-regulates antiapoptotic proteins and sensitizes human breast cancer cells to epothilone B-induced apoptosis. Cancer Res 2003; 63: 93–99.

    Google Scholar 

  30. Tao W, South VJ, Zhang Y, Davide JP, Farrell L, Kohl NE et al. Induction of apoptosis by an inhibitor of the mitotic kinesin KSP requires both activation of the spindle assembly checkpoint and mitotic slippage. Cancer Cell 2005; 8: 49–59.

    Article  CAS  PubMed  Google Scholar 

  31. Lin S-F, Gao SP, Price DL, Li S, Chou TC, Singh P et al. Synergy of a herpes oncolytic virus and paclitaxel for anaplastic thyroid cancer. Clin. Cancer Res 2008; 14: 1519–1528.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Dr Martin Gullberg (Umeå University, Sweden) and Dr Patricia Schaffer (Harvard Medical School, Boston, MA) for very helpful advice and insightful discussions, and Melissa Marinelli for technical support with the mice studies. Fluorescent microscopy was performed in the Microscopy Core of the Program in Membrane Biology, which receives additional support from an Inflammatory Bowel Disease Center Grant DK43351 and a Boston Area Diabetes and Endocrinology Research Center Award DK57521.This study was in part supported by a grant to RLM (RO1 CA102139).

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Correspondence to B J Passer.

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Passer, B., Castelo-Branco, P., Buhrman, J. et al. Oncolytic herpes simplex virus vectors and taxanes synergize to promote killing of prostate cancer cells. Cancer Gene Ther 16, 551–560 (2009). https://doi.org/10.1038/cgt.2009.10

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  • DOI: https://doi.org/10.1038/cgt.2009.10

Keywords

  • prostate cancer
  • oncolytic HSV's
  • taxanes

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