Abstract
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.
Highlights
The metastasis of breast cancer to distant organs remains the most challenging aspect for the clinical management of this disease
histone deacetylase (HDAC) inhibitor LD50 values in breast cancer cells Prior to analyzing the effect of HDAC inhibitors on the replication of oncolytic herpes simplex virus (oHSV), it was first necessary to determine LD50 values since those have not been reported in the breast cancer cells used in this study for most of the inhibitors
The LD50 values were similar in all three cell lines and for most compounds were in the micromolar range
Summary
The metastasis of breast cancer to distant organs remains the most challenging aspect for the clinical management of this disease. While much of the initial interest in oHSV focused on its use as a therapy for brain tumors, an increasing number of preclinical studies have demonstrated that oHSVs can be effective against a variety of tumor types, including breast cancer. The safety of this approach has been established for several different cancers. These clinical trials have illustrated the need for greater antitumor efficacy For this reason, there is growing interest in the combination of oHSV with other treatment modalities, such as radiotherapy or chemotherapy, in an effort to enhance viral efficacy [6,7]
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