New therapies are needed for metastatic breast cancer patients. Oncolytic herpes simplex virus (oHSV) is an exciting therapy being developed for use against aggressive tumors and established metastases. Although oHSV have been demonstrated safe in clinical trials, a lack of sufficient potency has slowed the clinical application of this approach. We utilized histone deacetylase (HDAC) inhibitors, which have been noted to impair the innate antiviral response and improve gene transcription from viral vectors, to enhance the replication of oHSV in breast cancer cells. A panel of chemically diverse HDAC inhibitors were tested at three different doses (<, = , and >LD50) for their ability to modulate the replication of oHSV in breast cancer cells. Several of the tested HDAC inhibitors enhanced oHSV replication at low multiplicity of infection (MOI) following pre-treatment of the metastatic breast cancer cell line MDA-MB-231 and the oHSV-resistant cell line 4T1, but not in the normal breast epithelial cell line MCF10A. Inhibitors of class I HDACs, including pan-selective compounds, were more effective for increasing oHSV replication compared to inhibitors that selectively target class II HDACs. These studies demonstrate that select HDAC inhibitors increase oHSV replication in breast cancer cells and provides support for pre-clinical evaluation of this combination strategy.
References
[1]
Siegel R, Naishadham D, Jemal A (2013) Cancer statistics, 2013. CA Cancer J Clin 63: 11–30 10.3322/caac.21166 [doi].
[2]
Bowles EJ, Wellman R, Feigelson HS, Onitilo AA, Freedman AN, et al. (2012) Risk of heart failure in breast cancer patients after anthracycline and trastuzumab treatment: a retrospective cohort study. J Natl Cancer Inst 104: 1293–1305 djs317 [pii];10.1093/jnci/djs317 [doi].
[3]
Darby SC, Ewertz M, McGale P, Bennet AM, Blom-Goldman U, et al. (2013) Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med 368: 987–998 10.1056/NEJMoa1209825 [doi].
[4]
Russell SJ, Peng KW, Bell JC (2012) Oncolytic virotherapy. Nat Biotechnol 30: 658–670 nbt.2287 [pii];10.1038/nbt.2287 [doi].
[5]
Campadelli-Fiume G, De GC, Gatta V, Nanni P, Lollini PL, et al. (2011) Rethinking herpes simplex virus: the way to oncolytic agents. Rev Med Virol 21: 213–226 10.1002/rmv.691 [doi].
[6]
Kanai R, Wakimoto H, Cheema T, Rabkin SD (2010) Oncolytic herpes simplex virus vectors and chemotherapy: are combinatorial strategies more effective for cancer? Future Oncol 6: 619–634 10.2217/fon.10.18 [doi].
[7]
Ottolino-Perry K, Diallo JS, Lichty BD, Bell JC, McCart JA (2010) Intelligent design: combination therapy with oncolytic viruses. Mol Ther 18: 251–263 mt2009283 [pii];10.1038/mt.2009.283 [doi].
[8]
Smith KT, Workman JL (2009) Histone deacetylase inhibitors: anticancer compounds. Int J Biochem Cell Biol 41: 21–25 S1357-2725(08)00387-7 [pii];10.1016/j.biocel.2008.09.008 [doi].
[9]
Chang HM, Paulson M, Holko M, Rice CM, Williams BR, et al. (2004) Induction of interferon-stimulated gene expression and antiviral responses require protein deacetylase activity. Proc Natl Acad Sci U S A 101: 9578–9583 10.1073/pnas.0400567101 [doi];0400567101 [pii].
[10]
Chou J, Kern ER, Whitley RJ, Roizman B (1990) Mapping of herpes simplex virus-1 neurovirulence to gamma 134.5, a gene nonessential for growth in culture. Science 250: 1262–1266. doi: 10.1126/science.2173860
[11]
Katsura T, Iwai S, Ota Y, Shimizu H, Ikuta K, et al. (2009) The effects of trichostatin A on the oncolytic ability of herpes simplex virus for oral squamous cell carcinoma cells. Cancer Gene Ther 16: 237–245 cgt200881 [pii];10.1038/cgt.2008.81 [doi].
[12]
Liu TC, Castelo-Branco P, Rabkin SD, Martuza RL (2008) Trichostatin A and oncolytic HSV combination therapy shows enhanced antitumoral and antiangiogenic effects. Mol Ther 16: 1041–1047 mt200858 [pii];10.1038/mt.2008.58 [doi].
[13]
Otsuki A, Patel A, Kasai K, Suzuki M, Kurozumi K, et al. (2008) Histone deacetylase inhibitors augment antitumor efficacy of herpes-based oncolytic viruses. Mol Ther 16: 1546–1555 mt2008155 [pii];10.1038/mt.2008.155 [doi].
[14]
Hurst DR, Xie Y, Vaidya KS, Mehta A, Moore BP, et al. (2008) Alterations of BRMS1-ARID4A interaction modify gene expression but still suppress metastasis in human breast cancer cells. J Biol Chem 283: 7438–7444 M709446200 [pii];10.1074/jbc.M709446200 [doi].
[15]
Hurst DR, Xie Y, Edmonds MD, Welch DR (2009) Multiple forms of BRMS1 are differentially expressed in the MCF10 isogenic breast cancer progression model. Clin Exp Metastasis 26: 89–96 10.1007/s10585-008-9216-9 [doi].
[16]
Parker JN, Gillespie GY, Love CE, Randall S, Whitley RJ, et al. (2000) Engineered herpes simplex virus expressing IL-12 in the treatment of experimental murine brain tumors. Proc Natl Acad Sci U S A 97: 2208–2213 10.1073/pnas.040557897 [doi] 040557897 [pii].
[17]
Andreansky S, He B, van Cott J, McGhee J, Markert JM, et al. (1998) Treatment of intracranial gliomas in immunocompetent mice using herpes simplex viruses that express murine interleukins. 1998/04/16: 121–130 10.1038/sj.gt.3300550. doi: 10.1038/sj.gt.3300550
[18]
Cody JJ, Scaturro P, Cantor AB, Yancey GG, Parker JN, et al. (2012) Preclinical evaluation of oncolytic deltagamma(1)34.5 herpes simplex virus expressing interleukin-12 for therapy of breast cancer brain metastases. Int J Breast Cancer 2012: 628697 10.1155/2012/628697 [doi].
[19]
Thomas DL, Fraser NW (2003) HSV-1 therapy of primary tumors reduces the number of metastases in an immune-competent model of metastatic breast cancer. 8: : 543–551. S1525001603002363 [pii].
[20]
Hellums EK, Markert JM, Parker JN, He B, Perbal B, et al. (2005) Increased efficacy of an interleukin-12-secreting herpes simplex virus in a syngeneic intracranial murine glioma model. Neuro Oncol 7: 213–224 10.1215/S1152851705000074. doi: 10.1215/s1152851705000074
Markert JM, Medlock MD, Rabkin SD, Gillespie GY, Todo T, et al. (2000) Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial. Gene Ther 7: 867–874 10.1038/sj.gt.3301205. doi: 10.1038/sj.gt.3301205
[23]
Markert JM, Liechty PG, Wang W, Gaston S, Braz E, et al.. (2009) Phase Ib trial of mutant herpes simplex virus G207 inoculated pre-and post-tumor resection for recurrent GBM. Mol Ther 17: : 199–207. mt2008228 [pii] 10.1038/mt.2008.228.
[24]
Alvarez-Breckenridge CA, Yu J, Price R, Wei M, Wang Y, et al. (2012) The histone deacetylase inhibitor valproic acid lessens NK cell action against oncolytic virus-infected glioblastoma cells by inhibition of STAT5/T-BET signaling and generation of gamma interferon. J Virol 86: 4566–4577 JVI.05545-11 [pii];10.1128/JVI.05545-11 [doi].
[25]
Nguyen TL, Abdelbary H, Arguello M, Breitbach C, Leveille S, et al. (2008) Chemical targeting of the innate antiviral response by histone deacetylase inhibitors renders refractory cancers sensitive to viral oncolysis. Proc Natl Acad Sci U S A 105: 14981–14986 0803988105 [pii];10.1073/pnas.0803988105 [doi].
[26]
MacTavish H, Diallo JS, Huang B, Stanford M, Le BF, et al. (2010) Enhancement of vaccinia virus based oncolysis with histone deacetylase inhibitors. PLoS One 5: e14462 10.1371/journal.pone.0014462 [doi].
[27]
Nguyen TL, Wilson MG, Hiscott J (2010) Oncolytic viruses and histone deacetylase inhibitors—a multi-pronged strategy to target tumor cells. Cytokine Growth Factor Rev 21: 153–159 S1359-6101(10)00027-4 [pii];10.1016/j.cytogfr.2010.03.002 [doi].
