Chaetocin is a fungal mycotoxin that inhibits HMTs. Blood Advances 3 (4), 508–518. Advances in the development of histone lysine demethylase inhibitors. Semin. Hypermethylation-mediated silencing of genes in CRC has been widely studied. doi: 10.1093/embo-reports/kvf053, Eckschlager, T., Plch, J., Stiborova, M., Hrabeta, J. Biol 28 (2), 752–771. Advanced stage cancers are characterized by metastasis, which includes cell migration, invasion, and angiogenesis. 1,107 total views, 1 views today. (2015). The effect of zebularine on CRC has also been investigated. This was paralleled by decreased signaling through the MAPK and PI3K/AKT pathways. Biol. 82 (7), 1159–1164. (2017). The epigenome is tremendously complex; hence, it is needed to minimize the off-target effects of epigenetic modifying drugs. J. Mol. Res. Clipboard, Search History, and several other advanced features are temporarily unavailable. It was shown to reduce the growth of HCC cells by inhibiting the proliferation with its specificity for class I HDACs (Mandl-Weber et al., 2010). Epigenetics and Other Cancer Treatments. Zebularine-treated cumulus cells were found with reduced overall DNA methylation patterns and gene-specific DNA methylation levels at the promoter regions of pluripotency genes (Oct4, Sox2, and Nanog), which indicates that zebularine has a role to play in the case of cancer stem cells (Rao et al., 2007). The four epigenetic drugs available for clinical use in the U.S. include two DNA demethylating agents, 5-azacytidine and decitabine, and two histone deacetylase (HDAC) inhibitors, vorinostat and valproic acid. Int. (2018). Low expression of NALP1 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 1) is associated with survival and tumor metastasis in colon cancer. Veda ... Epigenetic drugs have primarily been studied for their use in treating cancer, however research on their use in Alzheimer’s, Asthma and a myriad of other CNS, CVS, inflammatory/immune diseases is steadily rising. Cancer Ther. Epigenetic aberrations affect every aspect of tumor development from initiation to metastasis. DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. doi: 10.1177/1535370215583800, Michaud, D. S., Spieg lman, D., Clinton, S. K., Rimm, E. B., Willett, W. C., Giovannucci, E. L. (1999). 433 (1–2), 141–148. Analysis of gene expression profiles of CRC cell lines treated with panobinostat revealed alteration of genes involved in the process of angiogenesis, mitosis, DNA replication, and apoptosis (Regel et al., 2012). (2019). doi: 10.1002/pros.21247. MGMT promoter methylation status in brain metastases from colorectal cancer and corresponding primary tumors. Mol. Clin Epigenetics. Pharm. 7 (2), e2098. Disulfiram-mediated inhibition of NF-κB activity enhances cytotoxicity of 5-fluorouracil in human colorectal cancer cell lines. 60 (4), 419. doi: 10.4103/0019-5154.160511, Butler, L. M., Zhou, X., Xu, W. S., Scher, H. I., Rifkind, R. A., Marks, P. A., et al. In fact, suberanilohydroxamic acid (SAHA) has been shown to inhibit HDAC at very minimal concentration (Guo and Zhang, 2012). It revealed the selective function of SFNs for benign hyperplastic and cancer but not normal cells (Clarke et al., 2011). For example, Vorinostat (SAHA), romodepsin, belinostat, and panobinostat are the potent HDACi, approved for cancer therapy by FDA (Eckschlager et al., 2017). Accessibility Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. 4SC-202 (domatinostat) is an orally administered small molecule for the treatment of various types of cancer. HDAC inhibitors as epigenetic regulators of the immune system: Impacts on cancer therapy and inflammatory diseases. Treatment of chaetocin reduces cell growth by downregulating Blimp1 and RANKL (receptor activator of NFκB ligand) expression, which reduces osteoclast differentiation. Generation of cancer stem cells is associated with acetylation. Vorinostat acts indirectly under hypoxic conditions, suppressing hypoxia inducible factor (HIF)-1 alpha and vascular endothelial growth factor (VEGF), and thus blocks angiogenesis (Zhijun et al., 2016). View all Meanwhile, various inhibitor drugs, such as FK228, SAHA and MS-275, have already been the focus of phase III clinical experiments. The anticancer effect of chaetocin is enhanced by inhibition of autophagy. J. Haematol. Sulforaphane enhances the therapeutic potential of TRAIL in prostate cancer orthotopic model through regulation of apoptosis, metastasis, and angiogenesis. doi: 10.4172/2157-7633.S7-006, Sato, S., Katsushima, K., Shinjo, K., Hatanaka, A., Ohka, F., Suzuki, S., et al. 1. Several lines of evidences have demonstrated that the aberrant expression of HDACs is often associated with poor prognosis as well as poor survival rates in CRC. It is a new potential therapeutic drug used for the treatment of cancer (Richon et al., 1998; Bubna, 2015). It differs from decitabine in the way that it can bind to both DNA and RNA, whereas decitabine can bind only to the DNA. 91 (7), 605–613. Epigenetic Drug Against Mantle Cell Lymphoma Esteller’s team recently produced a first-in-class inhibitor of the histone deacetylase 6 (HDAC6) that among hundreds of different types of cancer cells showed a higher activity for a subtype of lymphoma called mantle cell lymphoma (MCL). Nucleosidic DNA demethylating epigenetic drugs - A comprehensive review from discovery to clinic DNA methylation plays a pivotal role in the etiology of cancer by mediating epigenetic silencing of … Conversely, HDACs catalyze histone deacetylation, resulting in chromatin condensation and transcriptional repression (Eberharter and Becker, 2002). (2012). Induction of p21 protein protects against sulforaphane-induced mitotic arrest in LNCaP human prostate cancer cell line. The inherent plastic nature of epigenetic changes provides possible lines for targeted treatment using specific inhibitors for proteins involved in epigenetic modifications. 32 (6), 910–912. Biophys. One of the major regulatory cascades in the case of CRC is the Wnt/β-catenin signaling pathway, which is also controlled by epigenetic mechanism (Zhang et al., 2018). 94, 813–819. Epigenetic Approaches to the Treatment of Dental Pulp Inflammation and Repair: Opportunities and Obstacles. Tumor Biol. Epigenet. Loss of SMAR1 leads to enriched H3K9 acetylation of the β-catenin promoter that further activates the Wnt/β-catenin signaling pathway and CRC progression (Taye et al., 2018). Azacitidine (marketed as Vidaza) is basically a ribonucleoside and functions as a chemical analog of cytidine. Adv. CRCs that are positive for CIMP are rich in hypermethylation in CpG island of panel of marker genes CRABP1, SOCS1, RUNX3, MLH1, CACNA1G, NEUROG1, CDKN2A, and IGF2 (Bae et al., 2017). JADE3 interacts with the promoters of LGR5 (colon stem cell marker) and activates its transcription by increasing the occupancy of p300 acetyltransferase and histone acetylation, hence substantially inducing Wnt/β-catenin signaling (Jian et al., 2018). 12 (15), 4628–4635. Belinostat exerts antitumor cytotoxicity through the ubiquitin–proteasome pathway in lung squamous cell carcinoma. 10 (6), 935–954. It was developed by TopoTarget for the treatment of hematological malignancies and solid tumors. Anticancer Res. doi: 10.1093/carcin/bgp073, Dixit, D., Ghildiyal, R., Anto, N. P., Sen, E. (2014). Dev. J. Med. Cancer Chemother. Epigenetic side-effects of common pharmaceuticals: a potential new field in medicine and pharmacology. HDAC up-regulation in early colon field carcinogenesis is involved in cell tumorigenicity through regulation of chromatin structure. Differential effects of sulforaphane on histone deacetylases, cell cycle arrest and apoptosis in normal prostate cells versus hyperplastic and cancerous prostate cells. SAHA increases expression of TATA Box binding protein-2 (TBP-2) that inhibits thioredoxin, which is an intracellular antioxidant in prostate, bladder, and breast cancer cells. Panobinostat treatment increases acetylated H3 and H4 as well as non-histone proteins HIF-1α, α-tubulin, β-catenin, chaperons (HSP90), estrogen receptor (ERα), androgen receptor (AR), signaling mediators (Stat3, Smad7), DNA repair proteins (Ku70), retinoblastoma protein (pRb), etc., leading to alterations in transcriptional factors (p53, E2F, NF-кB, c-Myc) (Singh et al., 2010; Kim and Bae, 2011; Jones et al., 2011). doi: 10.1016/j.jhep.2016.02.043, Borodovsky, A., Salmasi, V., Turcan, S., Fabius, A. W., Baia, G. S., Eberhart, C. G., et al. Curr. The epigenome is highly regulated and complex; therefore, it is important that off-target effects of epigenetic drugs be minimized. Their anticancer properties and natural abundance make them a great candidate for drug development. doi: 10.1016/j.actatropica.2017.02.007, Keywords: drugs, histone, colorectal cancer, therapy, epigenetics, Citation: Patnaik S and Anupriya (2019) Drugs Targeting Epigenetic Modifications and Plausible Therapeutic Strategies Against Colorectal Cancer. Nat. Stem cells reside at the base of the colonic crypts, which is maintained in their native undifferentiated state through Wnt/β-catenin signaling. Resminostat is also used with the combination of other drugs for better efficacy like sorafenib and docetaxel (Bitzer et al., 2016; Mandl-Weber et al., 2010). doi: 10.1016/j.canlet.2009.02.019, Bae, J. S., Han, M., Yao, C., Chung, J. H. (2016). Biochem Soc. Deviant histone methylations have been suggested to play a major role in CRC. 37 (26), 3485–3500. This finding suggests that hypermethylation of certain genes occurring at the early stage of CRC could provide promising diagnostic biomarkers. Figure reproduced with permission from Elsevier through RightsLink Copyright Clarence Center [82]. Epigenetic drugs, their targets and clinical status are presented. Juengel, E., Erb, H. H., Haferkamp, A., Rutz, J., Chun, F. K. H., Blaheta, R. A. It markedly induces p21 expression and significantly attenuates cell proliferation. Life Sci. PloS One 8 (5), e64600. Pharmacol. Upregulated expression of HDAC2 is found in the early stages in CRC along with HDAC1–3, HDAC5, and HDAC7 (Stypula-Cyrus et al., 2013). Biol. View Articles. It engages the DNMTs by binding to it irreversibly through a covalent bond and inhibiting the methylation of a daughter strand during the replication (Jabbour et al., 2008). Curr. Sulforaphane (SFN) is a natural compound found in cruciferous vegetables from the Brassicaceae family like broccoli, cauliflower, Brussels sprouts, and cabbage. J. Biol. Overall, HDACi reduce metastasis by reducing the expression of genes involved in migration, angiogenesis, epithelial-to-mesenchymal transition (EMT), and cell survival while enhancing the expression of genes involved in apoptosis (Figure 1). During chemotherapy, cancer stem cells are a small population of cells that escape and enter into the dormancy phase, slow the growth rate, and resemble normal stem cell properties. Advantages of using a delivery method for epigenetic drugs as well as examples of current advancements and challenges are also discussed. The nanoparticles are taken into the cell by pinocytosis and enter an endosome. This results in poor cell survival and reduced metastasis. (2017). Promoter CpG island hypermethylation- and H3K9me3 and H3K27me3-mediated epigenetic silencing targets the deleted in colon cancer (DCC) gene in colorectal carcinogenesis without affecting neighboring genes on chromosomal region 18q21. 9 (2), 85. doi: 10.3969/j.issn.2095-3941.2012.02.001, Hayashi, A., Horiuchi, A., Kikuchi, N., Hayashi, T., Fuseya, C., Suzuki, A., et al. Zebularine induces replication-dependent double-strand breaks which are preferentially repaired by homologous recombination. doi: 10.1007/978-3-642-01222-8_11. Overall, it helps in the restoration of cancer cell sensitivity toward drugs and body immunity (cytotoxic lymphocytes) and most importantly reverses the EMT. and permissive chromatin: Second in review series on chromatin dynamics. Most of the drugs mentioned in this review are FDA-approved as they work efficiently in specific cancers at certain stages of the disease. Kras gene mutation and RASSF1A, FHIT and MGMT gene promoter hypermethylation: Indicators of tumor staging and metastasis in adenocarcinomatous sporadic colorectal cancer in Indian population. Treatment of cancer cell lines with chaetocin led to downregulation of SUV39H1 along with reduction in H3K9 status (Cherblanc et al., 2013; Chiba et al., 2015). Targeting class I histone deacetylases by the novel small molecule inhibitor 4 SC-202 blocks oncogenic hedgehog-GLI signaling and overcomes smoothened inhibitor resistance. Commun. J. Nanomedicine 12, 8427. doi: 10.2147/IJN.S147659, Brunetto, A. T., Ang, J. E., Lal, R., Olmos, D., Molife, L. R., Kristeleit, R., et al. The drugs … doi: 10.1136/jmg.38.5.285, Coyle, K. M., Boudreau, J. E., Marcato, P. (2017). Mol. Oncol. SFN is well known to suppress HDACs, which alter epigenetic regulation. There are so many potential HDACi in the market. Ezh2-mediated trimethylation of lysine 27 of histone 3 (H3K27me3) leads to inactivation of tumor suppressor genes and hence increases EMT phenotype and malignancy (Tiwari et al., 2013). doi: 10.1158/0008-5472.CAN-07-0912, Lin, J., Haffner, M. C., Zhang, Y., Lee, B. H., Brennen, W. N., Britton, J., et al. Alumkal, J. J., Slottke, R., Schwartzman, J., Cherala, G., Munar, M., Graff, J. N., et al. Hypermethylation of the promoter region of APC causes its inactivation, which leads to the accumulation of β-catenin. doi: 10.1016/j.molonc.2012.07.003, Beck, H. C., Petersen, J., Nielsen, S. J., Morszeck, C., Jensen, P. B., Sehested, M., et al. The novel inhibitor of histone deacetylase resminostat (RAS2410) inhibits proliferation and induces apoptosis in multiple myeloma (MM) cells. Inhibition of histone deacetylase 7 reverses concentrative nucleoside transporter 2 repression in colorectal cancer by up-regulating histone acetylation state. 38 (7), 787. doi: 10.1038/ng1834. Their findings were published in the journal Haematologica. Overexpression of HDACs has been shown to promote migration, invasion, tumorigenesis, and metastasis. Colorectal cancer (CRC) is the third most common cancer in men and the second most common in women with expected increase in burden by 60% in the coming 10 years (Arnold et al., 2017). doi: 10.1248/bpb.b15-00129, Taye, N., Alam, A., Ghorai, S., Chatterji, D. G., Parulekar, A., Mogare, D., et al. Mol. (2002). (2012). Cancer Prev. Epigenetic drugs, their targets and clinical status are presented. doi: 10.1007/s10637-014-0189-z, PubMed Abstract | CrossRef Full Text | Google Scholar. 1842 (7), 971–980. Gastroenterol. doi: 10.1016/j.ccr.2013.04.020, Tumber, A., Collins, L. S., Petersen, K. D., Thougaard, A., Christiansen, S. J., Dejligbjerg, M., et al. 60 (1), 44–53. doi: 10.7534/j.issn.1009-2137.2017.01.014, Lin, E. Y., Pollard, J. W. (2007). Expert Opin Drug Metab Toxicol. 40 (8), 1320–1325. doi: 10.1007/s00280-006-0374-7, Vaiopoulos, A. G., Athanasoula, K. C., Papavassiliou, A. G. (2014). Acad. Cancer Lett. A., de Oliv ira Santos, J., Mendes, I., de Souza, W., Machado, C. R., Motta, M. C. M. (2017). It induces suppression of the Wnt signaling pathway by decreasing β-catenin protein levels in cholangiocarcinoma (CCA) cell lines TFK-1 and HuCCT1, which leads to apoptotic cell death in CCA (Yang et al., 2013). During replication, azacytidine gets incorporated into DNA. Treatment with both DNMT and HDACi restored the tumor suppressor genes’ activity (Rönsch et al., 2011). The first wave of epigenetic drugs: from phenotypic reality to epigenetic dreams All new therapeutic targets face challenges when tested in biological systems, but for epigenetic enzymes this is even more complex. Disulfiram has the ability to cross the blood–brain barrier and has been reported as a potential inhibitor of DNMT in several cancers. HDAC-regulated proteins include STAT3, tumor protein p53, Myc, RUNX3, β-catenin, EKLF, estrogen receptor, GATA family, HIF-1α, Foxp3, NF-Κb, and MyoD, which play major roles in cancer progression (Hull et al., 2016). Cancer 6 (1), 3. doi: 10.1186/1476-4598-6-3, Regel, Merkl, L., Fiedich, T., Burgermeister, E., Zimmermann, W., Einwächter, H., et al. It has also been used in combination with other drugs like tamoxifen, pembrolizumab, sorafenib, rituximab, and gefitinib for cancer treatment (Richon et al., 2000). Epigenetic drugs are divided according to their mechanisms and clinical phases that have been approved by the FDA or are undergoing evaluation phases. Cancer Prev. The handling editor declared a past co-authorship with one of the authors. (2017). DSF in combination with 5-fluorouracil (5-FU) is used as the major chemotherapeutic component for CRC. Recently, epigenetic modifications have been identified like association of hypermethylated gene Claudin11 (CLDN11) with metastasis and prognosis of poor survival of CRC. Unlike the inactive CDX1 locus, EPHB encoding DNA was hypomethylated in the promoter regions in silent state. A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases. 471 (2), 267–273. Cell 162 (5), 961–973. Currently, there are several potential drugs targeting HDACs and DNA/histone methyltransferases (DNMT/HMT) used in treating several types of cancer (Table 1). Cell Death Dis. doi: 10.1158/1940-6207.CAPR-14-0306, Jabbour, E., Issa, J. P., Garcia-Manero, G., Kantarjian, H. (2008). Cancer Res. BioMed Res. Cancers (Basel). Carcinog. The most well studied epigenetic modification in humans is DNA methylation; however it becomes increasingly acknowledged that DNA methylation does not work alone, but rather is linked to other modifications, such as histone modifications. Would you like email updates of new search results? doi: 10.1158/1078-0432.CCR-13-0735, Bubna, A. K. (2015). Cell. Biol. Chaetocin inhibits RANKL-induced osteoclast differentiation through reduction of Blimp1 in Raw264. doi: 10.1093/bfgp/ell028, Veverka, K. A., Johnson, K. L., Mays, D. C., Lipsky, J. J., Naylor, S. (1997). Basis Dis. Genetic and epigenetic alterations of colorectal cancer. Administration of azacytidine causes hypomethylation of the NDN promoter. H3K9me3 and H3K27me3 marks are associated with cancer progression and metastasis. (2017a). Biochem. Res. Its trade name is Dacogen. Mismatch repair gene promoter hypermethylation has been frequently observed in sporadic CRC with MSI while hypermethylation of the APC promoter is positively correlated with CRC metastasis (Van Engeland et al., 2011; Roy and Majumdar, 2012). Resminostat was seen to have anti-myeloma activity (Brunetto et al., 2013). DNA methyltransferase 1 (DNMT1) contains a reactive CXXC region (C is cysteine; X is any other amino acid) at its active site, which makes it susceptible to DSF (Syro et al., 2006). Cancer Lett. Cancer Sci. Areas covered: These findings suggested SFN activity in suppressing the cancer cell growth through increased histone acetylation (Myzak et al., 2007). It also lowers the required drug concentration during administration. LSD1: a viable therapeutic target in cutaneous squamous cell carcinoma? Clin Endocrinol. (2015). (2017). There is a section in the review with examples of diseases where epigenetic alterations lead to impaired pathways, with an emphasis on cancer. Glick, R. D., Swendeman, S. L., Coffey, D. C., Rifkind, R. A., Marks, P. A., Richon, V. M., et al. Pharmacol. 5-azacytidine reduces methylation, promotes differentiation and induces tumor regression in a patient-derived IDH1 mutant glioma xenograft. doi: 10.1158/1535-7163.MCT-06-0807, Hong, S. N. (2018). Hydrodynamic diameter and particle size distribution, and transmission electron microscopic analysis of the decitabine-loaded nanogels formulation. Biol. Sci. Role of miRNA-21/PTEN on the high glucose-induced EMT in human mesothelial peritoneal cells. Biol. A Review on “Triclosan A Controversial Antibacterial” » « Evaluation of Phytochemicals and Antioxidant Potential of Pomegranate Peel. Panobinostat, when used in combination with anthracyclines, works as a chemosensitizing agent for gastric cancer cells via activation of CITED2 (Cbp/p300-interacting transactivator 2) (Catalano et al., 2012). Chaetocin—A histone methyltransferase inhibitor—Impairs proliferation, arrests cell cycle and induces nucleolar disassembly in Trypanosoma cruzi. R01 CA149359/CA/NCI NIH HHS/United States. It comes within the isothiocyanate group of organosulfur compounds. Arnold, M., Sierra, M. S., Laversanne, M., Soerjomataram, I., Jemal, A., Bray, F. (2017). Combined treatment of lapatinib and panobinostat inhibits the proliferation and colony formation in all CRC cell lines tested. In multiple lung cancer cells, its treatment activates endoplasmic reticulum stress, which results in the upregulation of ER stress response proteins, transcription factor ATF3, and CHOP, which further contributes to apoptosis in a death receptor 5 (DR5)-dependent manner (Zhao et al., 2015a). It is therefore interesting that SFN intervenes with the cancer cells’ invasion cascade and angiogenesis by downregulating matrix metalloproteinases (MMP) such as MMP-1, MMP-2, MMP-7, and MMP-9 (Shankar et al., 2008). Cancer stem cells in colorectal cancer: Genetic and epigenetic changes. Chaetocin induces endoplasmic reticulum stress response and leads to death receptor 5-dependent apoptosis in human non-small cell lung cancer cells. Biochem. There are many more cases reporting acetylation related to the progression of CRC. doi: 10.1038/bcj.2015.37, Lee, E., Wang, J., Jung, Y., Cackowski, F. C., Taichman, R. S. (2018). Chaetocin inhibits IBMX-induced melanogenesis in B16F10 mouse melanoma cells through activation of ERK. DNA methylation of genes CMTM3, SSTR2, MDF1, NDRG4 and TGFB2 are potential epigenetic biomarkers for the early detection of CRC. Accumulation of β-catenin in enterocyte precursor results in retention of a stem cell phenotype, which prevents them from migrating to the surface to be sloughed off. doi: 10.1182/bloodadvances.2018027409, Gerecke, C., Schumacher, F., Edlich, A., Wetzel, A., Yealland, G., Neubert, L. K., et al. Treatment of cancer cells by this HDAC inhibitor induces ROS-dependent apoptosis (Lincoln et al., 2003; Lin and Pollard, 2007). doi: 10.1002/ijc.28985, Chowdhury, S., Howell, G. M., Teggart, C. A., Chowdhury, A., Person, J. J., Bowers, D. M., et al. It has been tested for several types of cancer including hematologic and solid malignancies, CTCL, Hodgkin’s lymphoma, leukemia, prostate, thyroid, and breast cancer (LaBonte et al., 2009). (2006). Figure 2 Depiction of mechanism of DNMT/HMT inhibitors as anticancer agents. Zhongguo shi yan xue ye xue za zhi 25 (1), 85–89.
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