HDAC/IKK inhibition therapies in solid tumors

Increased expression of the pro-angiogenic chemokine interleukin-8 (CXCL8, IL-8) contributes to the progression of solid cancers through its induction of tumor cell survival, proliferation, and metastasis. While histone deacetylase (HDAC) inhibitors have been remarkably effective in treating hematological malignancies, they have been far less effective as single agents in the treatment of solid tumors. We have recently reported results that may explain the limited efficiency of HDAC inhibitors in epithelial ovarian cancer (EOC), based on our data demonstrating that HDAC inhibition induces expression of IL-8 in EOC cells, resulting in their increased viability and proliferation, and that this is dependent on IκB kinase (IKK) activity [1]. Importantly, our in vivo results have demonstrated that combining HDAC and IKK inhibitors significantly reduces ovarian tumor growth when compared to either drug alone [1]. These data provide the first in vivo evidence demonstrating that IKK inhibition increases effectiveness of HDAC inhibitors in suppressing solid tumor growth, and suggesting that using IKK inhibitors may increase effectiveness of HDAC inhibitors in treating ovarian cancer and other solid tumors characterized by increased IL-8 expression (Figure 1). Even though HDAC expression is increased in many types of solid tumors, including EOC, clinical trials targeting the HDAC activity in solid tumors have been disappointing [2, 3]. The rationale for developing HDAC inhibitors as anti-cancer agents was based on their ability to induce hyperacetylation of histones and nonhistone proteins, resulting in increased differentiation, apoptosis, and cell cycle arrest of cancer cells [3, 4]. Vorinostat (suberoylanilide hydroxamic acid, Zolinza) and romidepsin (depsipeptide, FK228, Istodax) are the first HDACs inhibitors that have been approved by the FDA for the treatment of cutaneous T cell lymphoma. However, accumulating evidence indicates that HDAC inhibitors also activate the NFκB pro-survival pathway, which limits their lethality and contributes to drug resistance [5]. Interestingly, we have found that among the tested NFκB-regulated genes, only IL-8 is significantly induced by HDAC inhibition in EOC cells [1]. The induced IL-8 expression is associated with a gene specific, IKKdependent p65 NFκB recruitment to the IL-8 promoter. However, why HDAC inhibition induces p65 recruitment only to the IL-8 promoter in EOC cells? One possible scenario is that in EOC cells, the IL-8 promoter is Editorial