The rationale for developing HDACi
The rationale for developing HDACi as anticancer agents was based on their ability to induce the hyperacetylation of histones and nonhistone proteins, resulting in increased differentiation, apoptosis, and Protein A/G synthesis arrest of cancer cells 1, 2, 3. HDACi have been used in the treatment of hematological malignancies, since they exhibit excellent differential action on normal and cancer cells at therapeutic dosages 1, 2, 3. By contrast, clinical trials with HDACi as single agents in the treatment of solid tumors have produced disappointing results, but the specific responsible mechanisms are largely unknown. These mechanisms are likely multifactorial, and may include a limited distribution of HDACi in solid tumors, inactivation of specific antitumor immune responses, and increased expression of IKK-dependent proinflammatory and proangiogenic chemokines in solid cancer cells, thus limiting the effectiveness of HDACi in solid tumors. In this review, we specifically focus on the mechanisms of how HDACi induce the IKK-dependent transcription of proinflammatory and proangiogenic chemokines, particularly IL-8(CXCL8), in solid cancer cells, and on the opportunities for combination therapies targeting HDACs and IKK in solid tumors. Since HDACs class I, particularly HDAC1, 2, and 3, are involved in the HDACi-induced proinflammatory gene expression in solid tumor cells, we focus mainly on these HDACs.
HDACi are structurally diverse compounds that can be divided into several classes, including hydroxamates, cyclic peptides, aliphatic acids, ketones, and benzamides. As of 2017, four HDACi had been approved by the US Food and Drug Administration (FDA): vorinostat (suberoylanilide hydroxamic acid, SAHA, Zolinza), which was the first FDA-approved HDACi and has been used to treat cutaneous T cell lymphoma (CTCL); romidepsin (depsipeptide, FK228, Istodax), which has been used to treat CTCL and peripheral T cell lymphoma (PTCL); belinostat (PXD101, Beleodaq), approved for PTCL; and panobinostat (LBH589, Farydak), which has been used to treat patients with multiple myeloma (MM). In addition, other HDACi have been tested in preclinical studies and clinical trials, either as a monotherapy or in combination therapies. Since HDACi have many different, often opposing, cellular effects, combination therapies will likely be more effective than a monotherapy. Some HDACi, such as vorinostat, belinostat, and panobinostat, are nonselective (pan-inhibitors), and inhibit all HDACs, while other HDACi are class, or even isozyme specific. For example, romidepsin specifically inhibits class I HDACs, particularly HDAC1, 2, and 3 . Since HDACi induce hyperacetylation of histones and nonhistone proteins, they can reactivate tumor-suppressor genes and regulate key oncogenic signaling pathways. In addition to increasing the acetylation of histones, HDACi induce the acetylation of tumor suppressors, such as p53 and RUNX3, proto-oncogenes, including c-myc, and transcription factors involved in immune regulation and cancer signaling, such as the STAT transcription factors, hypoxia-inducible factor-1α (HIF-1α), Foxp3, and NFκB1, 5, 6, 7, 8, 9. By increasing the acetylation of histones and different transcription factors, HDACi can both induce and repress gene expression, thus providing an explanation for why so many genes are differentially regulated by HDACi. Gene expression-profiling studies have shown that HDACi affect the expression of approximately 2–10% of genes, with approximately equal number of genes being activated and suppressed 10, 11, 12. HDACi exhibit their anticancer effect by increasing expression of the cyclin-dependent kinase inhibitor p21, resulting in cell cycle arrest and differentiation; increasing apoptosis by upregulating proapoptotic genes and downregulating antiapoptotic genes; regulating DNA damage, reactive oxygen species (ROS) production, proteasome activity and DNA repair; and increasing endoplasmic reticulum (ER) stress and autophagy 2, 13. In addition, HDACi regulate the immune recognition of cancer cells by increasing the expression of MHC class I and II molecules 14, 15, inducing expression of PD-L1 16, 17, and promoting the differentiation and function of regulatory T cells .