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Abstract
BackgroundBortezomib, a proteasome inhibitor and suberoylanilide hydroxamic acid (SAHA, also known as Vorinostat), a histone deacetylase inhibitor, have been recognized as potent chemotherapeutic drugs. Bortezomib and SAHA are FDA-approved for the treatment of cutaneous T cell lymphoma and multiple myeloma/mantle cell lymphoma, respectively. Furthermore, the combination of the bortezomib and SAHA has been tested in a variety of preclinical models and in clinical trials and may be ideal for the treatment of cancer. However, it remains unclear how this treatment strategy affects the host immune response against tumors.ResultsHere, we used a well-defined E6/E7-expressing tumor model to examine how the immune system can be motivated to act against tumor cells expressing tumor antigens. We demonstrate that the combination of bortezomib and SAHA elicits potent antitumor effects in TC-1 tumor-bearing mice. Additionally, we are the first to show that treatment with bortezomib and SAHA leads to tumor-specific immunity by rendering tumor cells more susceptible to killing by antigen-specific CD8+ T cells than treatment with either drug alone.ConclusionsThe current study serves an important foundation for the future clinical application of both drugs for the treatment of cervical cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12929-014-0111-1) contains supplementary material, which is available to authorized users.
Highlights
Bortezomib, a proteasome inhibitor and suberoylanilide hydroxamic acid (SAHA, known as Vorinostat), a histone deacetylase inhibitor, have been recognized as potent chemotherapeutic drugs
We demonstrate that the combination of bortezomib and Suberoylanilide hydroxamic acid (SAHA) elicits potent antitumor effects in TC-1 tumor-bearing mice
We are the first to show that treatment with bortezomib and SAHA leads to tumor-specific immunity by rendering tumor cells more susceptible to killing by antigen-specific CD8+ T cells than treatment with either drug alone
Summary
Bortezomib, a proteasome inhibitor and suberoylanilide hydroxamic acid (SAHA, known as Vorinostat), a histone deacetylase inhibitor, have been recognized as potent chemotherapeutic drugs. The combination of the bortezomib and SAHA has been tested in a variety of preclinical models and in clinical trials and may be ideal for the treatment of cancer. It remains unclear how this treatment strategy affects the host immune response against tumors. Bortezomib is a proteasome inhibitor recognized as a potent chemotherapeutic agent that is currently used to treat relapsed multiple myeloma and mantle cell lymphoma (for review see [1]). We have previously elucidated the immune mechanism of the antitumor effects of bortezomib in an ovarian cancer model and found that bortezomib can be used to promote the generation of antigen-specific CD8+ T cells [4]. It is important to further elucidate this mechanism, to determine the utility of bortezomib as a therapeutic agent in additional cancer models, and to identify other therapeutic agents that may enhance the antitumor effects of bortezomib
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