HDAC Inhibitors as Anticancer Therapeutics

Abstract

Underlying mechanisms of carcinogenic aberrations in genome stems from genetic mutations and epigenetic modulations followed by a cascade of mechanistic events in signaling pathways. Acetylation status have been identified as one of the key markers of cancerous cells along with the over expression of Histone deacetylases (HDACs). In this context, HDACs are the focus of cancer research both from the cause and the treatment perspectives. HDAC inhibitors are one of the time-tested therapeutics and have recently been used as an effective adjuvant with the combination therapeutic regimens of cancers such as breast cancer. Here, we discuss the HDAC inhibitors as cancer treatment option in context with carcinogenic role of epigenetic modifications. This work is licensed under Creative Commons Attribution 4.0 License APPR.MS.ID.000508. Archives of Pharmacy & Pharmacology Research Volume 1-Issue 2 Citation: Sidra Shafique. HDAC Inhibitors as Anticancer Therapeutics. Arch Phar & Pharmacol Res. 1(2): 2018. APPR.MS.ID.000508. DOI: 10.33552/APPR.2018.01.000508. Page 2 of 3 progenitor-like cells and differentiated tumor cells. The two popular proposed models of Hierarchic CSC and Dynamic CSC models may largely determine the therapeutic response to cancer treatment and recurrence that in turn is largely directed by the epigenetic coding of these cells. Breast cancer studies have been proto-type to study the cancer stem cell identification, such as CD44+/CD24–, ALDH+ circulating stem cells phenotype play an important role in breast cancer metastasis [6]. Another example of epigenetic role in CSC is depressed immune response by immune system. Immune response to cancer cells by T cells occurs through the antigen processing genes (TAP). Epigenetic dysregulations in cancer stem cells have been shown by the downregulated expression of TAP genes due to DNA hypermethylation indicating the epigenetic modifications being a candidate niche for therapeutic targets and drug development [7]. HDACi as Prospective Cancer Therapeutics HDACs are shown to be over-expressed in various human tumors. HDAC I, II and III in gastric, breast and colorectal cancer. Therefore, HDACs have been studied as biomarkers of tumors to identify the normal tissue and also as the prognostic indicators such as prostate cancer [8]. HDACs are over-expressed in cancer cells and are considered to play a key role in cancer cells survival. HDAC 1, 2, 3 and 6 knock down induce cell cycle arrest and apoptosis in lung, breast and colon carcinomas thus advocating HDACi as promising cancer therapeutics [2]. HDAC classes include I, II, III and IV. HDACs in class III have NAD-dependent catalytic sites and have the overlapping functions with classical HDACs [2]. (West & Johnstone, 2014). HDAC downregulation and inhibition by small molecules such as SAHA, TSA and Valproic acid produce hyperacetylation of genome, for example HDAC3 deletion results in increased H3K9, K14ac; H4K5ac; and H4K12ac [9,10]. HDACi results in hyperacetylation which results in induction of apoptosis-inducing genes such as encoding the proapoptotic BMF indicating the interaction between apoptotic signaling pathways and the genetic modification. BMF is shown to play a central role in HDAC-mediated apoptosis [11]. The mechanistics of HDACi resulting in biological processes are not fully understood and largely depends on genetic signature of the tumor itself. Nevertheless, the most elucidated outcomes include differentiation, growth arrest, apoptosis induction, inhibition of angiogenesis and last but not the least immunogenicity. Around twenty clinically tested HDACi have been documented being effective in hematological malignancies such as multiple myeloma and acute myeloid leukemia. No HDACi has been seen effective as a monotherapy against cancer by now but mostly are used as an adjuvents in combination treatments [2]. HDACi are used as small molecule therapeutics in various diseases including malignancies. Based on the chemical structure, HDACi include hydroxamic acids (TSA (trichostatin A), vorinostat (SAHA), carboxylic acids (valproate, butyrate), aminobenzamides (entinostat), cyclic peptides (romidepsin) epoxyketones (trapoxins), and hybrid molecules. Out of these vorinostat and romidepsin have been approved for clinical use in cutaneous T cell lymphoma (CTCL), while active research is being on valproic acid and TSA [2]. Vorinostat (SAHA) is a pan HDAC inhibitor that modifies the acetylation status and induces apoptosis [12]. HDAC not only acetylate the histones but also affect the acetylation and thus activation status of non-histone proteins. Therefore, evidence suggests that HDACi are also effective in cancer therapy through this mechanism of action. Thus, SAHA increases the acetylation of heatshock protein 90 (HSP90) in HER2-overexpressing breast cancer cell lines. The acetylated HSP90 is dissociated from HER2 resulting in the degradation of HER2 [13]. Similarly, Valproic acid affects relatively better against HER2-overexpressing breast cancer cells than HER2-negative [14]. HDAC inhibitors have proven relatively successful for the treatment of hematological malignancies as compared to solid tumors. Therefore, these are used as an adjunct with current regimens of chemotherapies.