{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T18:04:31Z","timestamp":1787162671992,"version":"build-2736575974"},"reference-count":186,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,7,4]],"date-time":"2021-07-04T00:00:00Z","timestamp":1625356800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Myelodysplastic Syndromes (MDSs) affect the elderly and can progress to Acute Myeloid Leukemia (AML). Epigenetic alterations including DNA methylation and chromatin modification may contribute to the initiation and progression of these malignancies. DNA hypomethylating agents such as decitabine and azacitidine are used as therapeutic treatments and have shown to promote expression of genes involved in tumor suppression, apoptosis, and immune response. Another anti-cancer drug, the proteasome inhibitor bortezomib, is used as a chemotherapeutic treatment for multiple myeloma (MM). Phase III clinical trials of decitabine and azacitidine used alone and in combination with other chemotherapeutics demonstrated their capacity to treat hematological malignancies and prolong the survival of MDS and AML patients. Although phase III clinical trials examining bortezomib\u2019s role in MDS and AML patients are limited, its underlying mechanisms in MM highlight its potential as a chemotherapeutic for such malignancies. Further research is needed to better understand how the epigenetic mechanisms mediated by these chemotherapeutic agents and their targeted gene networks are associated with the development and progression of MDS into AML. This review discusses the mechanisms by which decitabine, azacitidine, and bortezomib alter epigenetic programs and their results from phase III clinical trials.<\/jats:p>","DOI":"10.3390\/ph14070641","type":"journal-article","created":{"date-parts":[[2021,7,4]],"date-time":"2021-07-04T22:34:36Z","timestamp":1625438076000},"page":"641","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Hypomethylating Chemotherapeutic Agents as Therapy for Myelodysplastic Syndromes and Prevention of Acute Myeloid Leukemia"],"prefix":"10.3390","volume":"14","author":[{"given":"Vincent G.","family":"Sorrentino","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, Rutgers University\u2014Newark, Newark, NJ 07102, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7503-6807","authenticated-orcid":false,"given":"Srijan","family":"Thota","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Rutgers University\u2014Newark, Newark, NJ 07102, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward A.","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Rutgers University\u2014Newark, Newark, NJ 07102, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0434-9034","authenticated-orcid":false,"given":"Pranela","family":"Rameshwar","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology\/Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor T.","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology\/Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA"},{"name":"Veteran Affairs New Jersey Health Care System, East Orange, NJ 07018, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Pierre","family":"Etchegaray","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Rutgers University\u2014Newark, Newark, NJ 07102, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Bond, D.R., Lee, H.J., and Enjeti, A.K. (2020). Unravelling the Epigenome of Myelodysplastic Syndrome: Diagnosis, Prognosis, and Response to Therapy. Cancers, 12.","DOI":"10.3390\/cancers12113128"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1007\/s11899-015-0269-y","article-title":"Incidence and Burden of the Myelodysplastic Syndromes","volume":"10","author":"Cogle","year":"2015","journal-title":"Curr. Hematol. Malig. Rep."},{"key":"ref_3","first-page":"783","article-title":"Myelodysplastic syndromes: Diagnosis, prognosis, and treatment","volume":"110","author":"Germing","year":"2013","journal-title":"Dtsch. Arztebl. Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1002\/ajh.24637","article-title":"Refractory anemia with ring sideroblasts (RARS) and RARS with thrombocytosis (RARS-T): 2017 update on diagnosis, risk-stratification, and management","volume":"92","author":"Patnaik","year":"2017","journal-title":"Am. J. Hematol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1182\/blood-2016-03-643544","article-title":"The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia","volume":"127","author":"Arber","year":"2016","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2454","DOI":"10.1182\/blood-2012-03-420489","article-title":"Revised international prognostic scoring system for myelodysplastic syndromes","volume":"120","author":"Greenberg","year":"2012","journal-title":"Blood"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Saultz, J.N., and Garzon, R. (2016). Acute Myeloid Leukemia: A Concise Review. J. Clin. Med., 5.","DOI":"10.3390\/jcm5030033"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/S0344-0338(11)80547-9","article-title":"Auer bodies in acute myeloid leukaemia patients","volume":"186","author":"Hassan","year":"1990","journal-title":"Pathol. Res. Pract."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1182\/blood-2018-10-844621","article-title":"Genetics of MDS","volume":"133","author":"Ogawa","year":"2019","journal-title":"Blood"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4325","DOI":"10.1182\/blood-2002-03-0772","article-title":"Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: Results from Cancer and Leukemia Group B (CALGB 8461)","volume":"100","author":"Byrd","year":"2002","journal-title":"Blood"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1158\/2159-8290.CD-19-0106","article-title":"Rational Targeting of Cooperating Layers of the Epigenome Yields Enhanced Therapeutic Efficacy against AML","volume":"9","author":"Duy","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2576","DOI":"10.1135\/cccc19642576","article-title":"Synthesis of a 2-deoxy-D-ribofuranosyl-5-azacytosine","volume":"29","author":"Pliml","year":"1964","journal-title":"Collect. Czech. Chem. Commun."},{"key":"ref_13","first-page":"1995","article-title":"Characteristics of mouse leukemic cells resistant to 5-azacytidine and 5-aza-2\u2032-deoxycytidine","volume":"28","author":"Sorm","year":"1968","journal-title":"Cancer Res."},{"key":"ref_14","first-page":"2673","article-title":"Effect of intravenous infusion of 5-aza-2\u2032-deoxycytidine on survival time of mice with L1210 leukemia","volume":"38","author":"Momparier","year":"1978","journal-title":"Cancer Res."},{"key":"ref_15","first-page":"3493","article-title":"Inhibition of DNA methylation in L1210 leukemic cells by 5-aza-2\u2032-deoxycytidine as a possible mechanism of chemotherapeutic action","volume":"43","author":"Wilson","year":"1983","journal-title":"Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s00277-005-0008-x","article-title":"Decitabine: A historical review of the development of an epigenetic drug","volume":"84","year":"2005","journal-title":"Ann. Hematol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1023\/A:1006388031954","article-title":"A phase I trial of cisplatin plus decitabine, a new DNA-hypomethylating agent, in patients with advanced solid tumors and a follow-up early phase II evaluation in patients with inoperable non-small cell lung cancer","volume":"18","author":"Schwartsmann","year":"2000","journal-title":"Investig. New Drugs"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1177\/030089169808400120","article-title":"A phase II study of 5-aza-2\u2032deoxycytidine (decitabine) in hormone independent metastatic (D2) prostate cancer","volume":"84","author":"Thibault","year":"1998","journal-title":"Tumori"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Hagemann, S., Heil, O., Lyko, F., and Brueckner, B. (2011). Azacytidine and decitabine induce gene-specific and non-random DNA demethylation in human cancer cell lines. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0017388"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.ccr.2009.11.020","article-title":"DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia","volume":"17","author":"Figueroa","year":"2010","journal-title":"Cancer Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1182\/blood-2006-05-021162","article-title":"Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia","volume":"109","author":"Kantarjian","year":"2007","journal-title":"Blood"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2341","DOI":"10.1002\/cncr.23463","article-title":"Evolution of decitabine development: Accomplishments, ongoing investigations, and future strategies","volume":"112","author":"Jabbour","year":"2008","journal-title":"Cancer"},{"key":"ref_23","first-page":"2989","article-title":"DNA methyltransferase inhibitors and their emerging role in epigenetic therapy of cancer","volume":"33","author":"Gnyszka","year":"2013","journal-title":"Anticancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2060","DOI":"10.1135\/cccc19642060","article-title":"Nucleic acids components and their analogues. Synthesis of 1-glycosyl derivatives of 5 azauracil and 5-azacytosine","volume":"29","year":"1964","journal-title":"Collect. Czech. Chem. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"991","DOI":"10.4155\/fmc.12.36","article-title":"5-azacytosine compounds in medicinal chemistry: Current stage and future perspectives","volume":"4","author":"Otmar","year":"2012","journal-title":"Future Med. Chem."},{"key":"ref_26","first-page":"619","article-title":"Microbiological production of 5-azacytidine. I. Production and biological activity","volume":"6","author":"Hanka","year":"1966","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3604","DOI":"10.1158\/1078-0432.CCR-04-2135","article-title":"Approval summary: Azacitidine for treatment of myelodysplastic syndrome subtypes","volume":"11","author":"Kaminskas","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1186\/s13643-018-0805-7","article-title":"A systematic review and network meta-analysis comparing azacitidine and decitabine for the treatment of myelodysplastic syndrome","volume":"7","author":"Almasri","year":"2018","journal-title":"Syst. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1680","DOI":"10.1038\/leu.2008.145","article-title":"A pilot pharmacokinetic study of oral azacitidine","volume":"22","author":"Stoltz","year":"2008","journal-title":"Leukemia"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"293","DOI":"10.2217\/fon.15.326","article-title":"Design of the randomized, Phase III, QUAZAR AML Maintenance trial of CC-486 (oral azacitidine) maintenance therapy in acute myeloid leukemia","volume":"12","author":"Roboz","year":"2016","journal-title":"Future Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"LBA-3","DOI":"10.1182\/blood-2019-132405","article-title":"The QUAZAR AML-001 Maintenance Trial: Results of a Phase III International, Randomized, Double-Blind, Placebo-Controlled Study of CC-486 (Oral Formulation of Azacitidine) in Patients with Acute Myeloid Leukemia (AML) in First Remission","volume":"134","author":"Wei","year":"2019","journal-title":"Blood"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"239","DOI":"10.2174\/156800911794519752","article-title":"Bortezomib as the first proteasome inhibitor anticancer drug: Current status and future perspectives","volume":"11","author":"Chen","year":"2011","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1634\/theoncologist.7-1-9","article-title":"Development of the proteasome inhibitor PS-341","volume":"7","author":"Adams","year":"2002","journal-title":"Oncologist"},{"key":"ref_34","first-page":"1","article-title":"Mechanism of action of bortezomib in multiple myeloma thera","volume":"6","author":"Ri","year":"2016","journal-title":"Int. J. Myeloma"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/nrc1361","article-title":"The proteasome: A suitable antineoplastic target","volume":"4","author":"Adams","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1652","DOI":"10.1126\/science.274.5293.1652","article-title":"How proteolysis drives the cell cycle","volume":"274","author":"King","year":"1996","journal-title":"Science"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1016\/0092-8674(94)90379-4","article-title":"p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest","volume":"76","author":"Kaufmann","year":"1994","journal-title":"Cell"},{"key":"ref_38","first-page":"2615","article-title":"Proteasome inhibitors: A novel class of potent and effective antitumor agents","volume":"59","author":"Adams","year":"1999","journal-title":"Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1002\/ajh.24746","article-title":"An exploratory clinical trial of bortezomib in patients with lower risk myelodysplastic syndromes","volume":"92","author":"Daher","year":"2017","journal-title":"Am. J. Hematol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/j.leukres.2006.05.018","article-title":"Bortezomib is an effective agent for MDS\/MPD syndrome with 5q\u2212 anomaly and thrombocytosis","volume":"31","author":"Terpos","year":"2007","journal-title":"Leuk. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2487","DOI":"10.1056\/NEJMoa043445","article-title":"Bortezomib or high-dose dexamethasone for relapsed multiple myeloma","volume":"352","author":"Richardson","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"100663","DOI":"10.1016\/j.drup.2019.100663","article-title":"Targeting the ubiquitin-proteasome pathway to overcome anti-cancer drug resistance","volume":"48","author":"Narayanan","year":"2020","journal-title":"Drug Resist. Updat."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/ijc.23607","article-title":"Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine","volume":"123","author":"Stresemann","year":"2008","journal-title":"Int. J. Cancer"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"S9","DOI":"10.1053\/j.seminhematol.2005.05.002","article-title":"Pharmacology of 5-Aza-2\u2032-deoxycytidine (decitabine)","volume":"42","author":"Momparler","year":"2005","journal-title":"Semin. Hematol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/0092-8674(80)90237-8","article-title":"Cellular differentiation, cytidine analogs and DNA methylation","volume":"20","author":"Jones","year":"1980","journal-title":"Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1358\/dof.2013.38.8.1980499","article-title":"SGI-110: DNA Methyltransferase Inhibitor Oncolytic","volume":"38","author":"Griffiths","year":"2013","journal-title":"Drugs Future"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"6993","DOI":"10.1073\/pnas.81.22.6993","article-title":"Covalent bond formation between a DNA-cytosine methyltransferase and DNA containing 5-azacytosine","volume":"81","author":"Santi","year":"1984","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"5483","DOI":"10.1038\/sj.onc.1205699","article-title":"5-Azacytidine and 5-aza-2\u2032-deoxycytidine as inhibitors of DNA methylation: Mechanistic studies and their implications for cancer therapy","volume":"21","author":"Christman","year":"2002","journal-title":"Oncogene"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1053\/j.seminoncol.2005.07.002","article-title":"Clinical development of decitabine as a prototype for an epigenetic drug program","volume":"32","author":"Rosenfeld","year":"2005","journal-title":"Semin. Oncol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2823","DOI":"10.1182\/blood.V97.9.2823","article-title":"Methylation profiling in acute myeloid leukemia","volume":"97","author":"Toyota","year":"2001","journal-title":"Blood"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/j.leukres.2004.11.014","article-title":"Methylation of p15(INK4b) and E-cadherin genes is independently correlated with poor prognosis in acute myeloid leukemia","volume":"29","author":"Shimamoto","year":"2005","journal-title":"Leuk. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1111\/cts.12861","article-title":"DNA Methylation-Based Epigenetic Repression of SLC22A4 Promotes Resistance to Cytarabine in Acute Myeloid Leukemia","volume":"14","author":"Buelow","year":"2021","journal-title":"Clin. Transl. Sci."},{"key":"ref_53","first-page":"454","article-title":"Decitabine treatment sensitizes tumor cells to T-cell-mediated cytotoxicity in patients with myelodysplastic syndromes","volume":"9","author":"Zhang","year":"2017","journal-title":"Am. J. Transl. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"5753","DOI":"10.1007\/s13277-014-1764-9","article-title":"Decitabine facilitates immune recognition of sarcoma cells by upregulating CT antigens, MHC molecules, and ICAM-1","volume":"35","author":"Krishnadas","year":"2014","journal-title":"Tumour Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1002\/ajh.24016","article-title":"Comparison of epigenetic versus standard induction chemotherapy for newly diagnosed acute myeloid leukemia patients \u226560 years old","volume":"90","author":"Gupta","year":"2015","journal-title":"Am. J. Hematol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1182\/blood.V106.11.495.495","article-title":"Decitabine: Where Is the Target?","volume":"106","author":"Tamm","year":"2005","journal-title":"Blood"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1053\/j.seminhematol.2012.08.001","article-title":"Clinical results with the DNA hypomethylating agent 5-aza-2\u2032-deoxycytidine (decitabine) in patients with myelodysplastic syndromes: An update","volume":"49","author":"Joeckel","year":"2012","journal-title":"Semin. Hematol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"6025","DOI":"10.1182\/blood-2012-03-413898","article-title":"Clinical and pharmacodynamic activity of bortezomib and decitabine in acute myeloid leukemia","volume":"119","author":"Blum","year":"2012","journal-title":"Blood"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1056\/NEJMoa1605949","article-title":"TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes","volume":"375","author":"Welch","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1514","DOI":"10.1182\/blood-2017-06-788497","article-title":"Randomized phase 2 study of low-dose decitabine vs. low-dose azacitidine in lower-risk MDS and MDS\/MPN","volume":"130","author":"Jabbour","year":"2017","journal-title":"Blood"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1007\/s12325-015-0263-8","article-title":"Decitabine for Treatment of Myelodysplastic Syndromes in Chinese Patients: An Open-Label, Phase-3b Study","volume":"32","author":"Wu","year":"2015","journal-title":"Adv. Ther."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2003","DOI":"10.1007\/s00277-015-2489-6","article-title":"Decitabine versus best supportive care in older patients with refractory anemia with excess blasts in transformation (RAEBt)\u2014Results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group (GMDSSG)","volume":"94","author":"Becker","year":"2015","journal-title":"Ann. Hematol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1794","DOI":"10.1002\/cncr.21792","article-title":"Decitabine improves patient outcomes in myelodysplastic syndromes: Results of a phase III randomized study","volume":"106","author":"Kantarjian","year":"2006","journal-title":"Cancer"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1007\/s00277-015-2547-0","article-title":"Decitabine improves progression-free survival in older high-risk MDS patients with multiple autosomal monosomies: Results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group","volume":"95","author":"Suciu","year":"2016","journal-title":"Ann. Hematol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1111\/bjh.14463","article-title":"Elevated fetal haemoglobin is a predictor of better outcome in MDS\/AML patients receiving 5-aza-2\u2032-deoxycytidine (Decitabine)","volume":"176","author":"Ihorst","year":"2017","journal-title":"Br. J. Haematol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1182\/blood.2019004143","article-title":"Oral cedazuridine\/decitabine for MDS and CMML: A phase 2 pharmacokinetic\/pharmacodynamic randomized crossover study","volume":"136","author":"Griffiths","year":"2020","journal-title":"Blood"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"19","DOI":"10.3389\/fonc.2017.00019","article-title":"Inhibition of DNA and Histone Methylation by 5-Aza-2\u2032-Deoxycytidine (Decitabine) and 3-Deazaneplanocin-A on Antineoplastic Action and Gene Expression in Myeloid Leukemic Cells","volume":"7","author":"Momparler","year":"2017","journal-title":"Front. Oncol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"3938","DOI":"10.1158\/1078-0432.CCR-08-2783","article-title":"Targeting DNA methylation","volume":"15","author":"Issa","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1182\/blood-2008-02-140038","article-title":"Mechanisms of resistance to 5-aza-2\u2032-deoxycytidine in human cancer cell lines","volume":"113","author":"Qin","year":"2009","journal-title":"Blood"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s13148-016-0237-y","article-title":"A clinical-molecular update on azanucleoside-based therapy for the treatment of hematologic cancers","volume":"8","author":"Diesch","year":"2016","journal-title":"Clin. Epigenet."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2705","DOI":"10.1182\/blood-2014-06-582809","article-title":"TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients","volume":"124","author":"Bejar","year":"2014","journal-title":"Blood"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1038\/leu.2013.269","article-title":"Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms","volume":"28","author":"Traina","year":"2014","journal-title":"Leukemia"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1038\/nrd3184","article-title":"Multifaceted polo-like kinases: Drug targets and antitargets for cancer therapy","volume":"9","author":"Strebhardt","year":"2010","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1158\/1078-0432.CCR-09-1380","article-title":"Targeting Polo-like kinase in cancer therapy","volume":"16","author":"Degenhardt","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.critrevonc.2015.10.013","article-title":"Polo-like kinase inhibitors in hematologic malignancies","volume":"98","author":"Talati","year":"2016","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Hollenbach, P.W., Nguyen, A.N., Brady, H., Williams, M., Ning, Y., Richard, N., Krushel, L., Aukerman, S.L., Heise, C., and MacBeth, K.J. (2010). A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0009001"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.2146\/ajhp040385","article-title":"Azacitidine: A novel agent for myelodysplastic syndromes","volume":"62","author":"Sullivan","year":"2005","journal-title":"Am. J. Health Syst. Pharm."},{"key":"ref_78","first-page":"1453","article-title":"The disposition and pharmacokinetics in humans of 5-azacytidine administered intravenously as a bolus or by continuous infusion","volume":"36","author":"Israili","year":"1976","journal-title":"Cancer Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1016\/j.tips.2010.08.001","article-title":"Targeting DNA methylation for epigenetic therapy","volume":"31","author":"Yang","year":"2010","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.2165\/11209430-000000000-00000","article-title":"Azacitidine: A review of its use in the management of myelodysplastic syndromes\/acute myeloid leukaemia","volume":"72","author":"Keating","year":"2012","journal-title":"Drugs"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"11018","DOI":"10.1021\/bi00110a002","article-title":"Direct identification of the active-site nucleophile in a DNA (cytosine-5)-methyltransferase","volume":"30","author":"Chen","year":"1991","journal-title":"Biochemistry"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"168","DOI":"10.4149\/neo_2012_022","article-title":"Monitoring of methylation changes in 9p21 region in patients with myelodysplastic syndromes and acute myeloid leukemia","volume":"59","author":"Cechova","year":"2012","journal-title":"Neoplasma"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2985","DOI":"10.1182\/blood.V91.8.2985.2985_2985_2990","article-title":"Methylation of the p15(INK4b) gene in myelodysplastic syndromes is frequent and acquired during disease progression","volume":"91","author":"Quesnel","year":"1998","journal-title":"Blood"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1182\/blood.V90.4.1403","article-title":"Hypermethylation of the p15INK4B gene in myelodysplastic syndromes","volume":"90","author":"Uchida","year":"1997","journal-title":"Blood"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1016\/S0145-2126(01)00054-6","article-title":"Re-evaluation of refractory anemia with excess blasts in transformation","volume":"25","author":"Ohyashiki","year":"2001","journal-title":"Leuk. Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"207","DOI":"10.3346\/jkms.2011.26.2.207","article-title":"DNA methylation changes following 5-azacitidine treatment in patients with myelodysplastic syndrome","volume":"26","author":"Tran","year":"2011","journal-title":"J. Korean Med. Sci."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1937","DOI":"10.1038\/sj.leu.2404796","article-title":"CDKN2B methylation status and isolated chromosome 7 abnormalities predict responses to treatment with 5-azacytidine","volume":"21","author":"Raj","year":"2007","journal-title":"Leukemia"},{"key":"ref_88","first-page":"795","article-title":"Antiproliferative and antitumor effects of azacitidine against the human myelodysplastic syndrome cell line SKM-1","volume":"32","author":"Kimura","year":"2012","journal-title":"Anticancer Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"16811","DOI":"10.1073\/pnas.0907109106","article-title":"Reduction of phosphoinositide-phospholipase C beta1 methylation predicts the responsiveness to azacitidine in high-risk MDS","volume":"106","author":"Follo","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1038\/sj.leu.2404855","article-title":"PI-PLC\u03b21 and activated Akt levels are linked to azacitidine responsiveness in high-risk myelodysplastic syndromes","volume":"22","author":"Follo","year":"2008","journal-title":"Leukemia"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1177\/2040620712464882","article-title":"Azacitidine in the management of patients with myelodysplastic syndromes","volume":"3","author":"Khan","year":"2012","journal-title":"Ther. Adv. Hematol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"3895","DOI":"10.1200\/JCO.2005.05.4346","article-title":"Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: Studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B","volume":"24","author":"Silverman","year":"2006","journal-title":"J. Clin. Oncol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2429","DOI":"10.1200\/JCO.2002.04.117","article-title":"Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: A study of the cancer and leukemia group B","volume":"20","author":"Silverman","year":"2002","journal-title":"J. Clin. Oncol."},{"key":"ref_94","first-page":"21","article-title":"Effects of treatment with 5-azacytidine on the in vivo and in vitro hematopoiesis in patients with myelodysplastic syndromes","volume":"7","author":"Silverman","year":"1993","journal-title":"Leukemia"},{"key":"ref_95","first-page":"489","article-title":"Fetal hemoglobin production in adult baboons by 5-azacytidine or by phenylhydrazine-induced hemolysis is associated with hypomethylation of globin gene DNA","volume":"134","author":"DeSimone","year":"1983","journal-title":"Prog. Clin. Biol. Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"3091","DOI":"10.1182\/blood.V81.11.3091.3091","article-title":"High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy","volume":"81","author":"Campos","year":"1993","journal-title":"Blood"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1038\/sj.leu.2402434","article-title":"The coexpression of the apoptosis-related genes bcl-2 and wt1 in predicting survival in adult acute myeloid leukemia","volume":"16","author":"Karakas","year":"2002","journal-title":"Leukemia"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"666","DOI":"10.4149\/neo_2013_085","article-title":"Overexpression of Bcl2 protein predicts chemoresistance in acute myeloid leukemia: Its correlation with FLT3","volume":"60","author":"Mehta","year":"2013","journal-title":"Neoplasma"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1056\/NEJMoa2012971","article-title":"Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia","volume":"383","author":"DiNardo","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1182\/blood-2015-01-621664","article-title":"International phase 3 study of azacitidine vs. conventional care regimens in older patients with newly diagnosed AML with >30% blasts","volume":"126","author":"Dombret","year":"2015","journal-title":"Blood"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1111\/j.1365-2141.2010.08235.x","article-title":"Maintenance treatment with azacytidine for patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy","volume":"150","author":"Karimi","year":"2010","journal-title":"Br. J. Haematol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.bmc.2009.10.044","article-title":"Acyclic nucleoside phosphonates with 5-azacytosine base moiety substituted in C-6 position","volume":"18","year":"2010","journal-title":"Bioorg. Med. Chem."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1007\/s12253-018-00574-0","article-title":"Real Life Data on Efficacy and Safety of Azacitidine Therapy for Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia and Acute Myeloid Leukemia","volume":"25","author":"Helbig","year":"2019","journal-title":"Pathol. Oncol. Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1126\/science.1083558","article-title":"Induction of tumors in mice by genomic hypomethylation","volume":"300","author":"Gaudet","year":"2003","journal-title":"Science"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1038\/sj.onc.1210631","article-title":"Activation and transposition of endogenous retroviral elements in hypomethylation induced tumors in mice","volume":"27","author":"Howard","year":"2008","journal-title":"Oncogene"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1158\/1535-7163.MCT-08-0743","article-title":"Human concentrative nucleoside transporter 1-mediated uptake of 5-azacytidine enhances DNA demethylation","volume":"8","author":"Rius","year":"2009","journal-title":"Mol. Cancer Ther."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.exphem.2013.12.004","article-title":"Mechanisms of resistance to azacitidine in human leukemia cell lines","volume":"42","author":"Sripayap","year":"2014","journal-title":"Exp. Hematol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"490","DOI":"10.18632\/oncotarget.481","article-title":"BCL2L10 is a predictive factor for resistance to azacitidine in MDS and AML patients","volume":"3","author":"Cluzeau","year":"2012","journal-title":"Oncotarget"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1038\/s41467-018-03513-4","article-title":"RNA cytosine methylation and methyltransferases mediate chromatin organization and 5-azacytidine response and resistance in leukaemia","volume":"9","author":"Cheng","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"3388","DOI":"10.1038\/s41375-020-0973-z","article-title":"Distinct and overlapping mechanisms of resistance to azacytidine and guadecitabine in acute myeloid leukemia","volume":"34","author":"Gruber","year":"2020","journal-title":"Leukemia"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/j.celrep.2017.06.067","article-title":"Integrative Genomics Identifies the Molecular Basis of Resistance to Azacitidine Therapy in Myelodysplastic Syndromes","volume":"20","author":"Unnikrishnan","year":"2017","journal-title":"Cell Rep."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1080\/13543784.2019.1667331","article-title":"Guadecitabine (SGI-110): An investigational drug for the treatment of myelodysplastic syndrome and acute myeloid leukemia","volume":"28","author":"Merchan","year":"2019","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.3324\/haematol.2018.207118","article-title":"A phase II study of guadecitabine in higher-risk myelodysplastic syndrome and low blast count acute myeloid leukemia after azacitidine failure","volume":"104","author":"Renneville","year":"2019","journal-title":"Haematologica"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1016\/S1470-2045(15)00038-8","article-title":"Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: A multicentre, randomised, dose-escalation phase 1 study","volume":"16","author":"Issa","year":"2015","journal-title":"Lancet Oncol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1016\/S1470-2045(17)30576-4","article-title":"Guadecitabine (SGI-110) in treatment-naive patients with acute myeloid leukaemia: Phase 2 results from a multicentre, randomised, phase 1\/2 trial","volume":"18","author":"Kantarjian","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.str.2005.11.019","article-title":"Crystal structure of the boronic acid-based proteasome inhibitor bortezomib in complex with the yeast 20S proteasome","volume":"14","author":"Groll","year":"2006","journal-title":"Structure"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"4907","DOI":"10.1182\/blood-2005-08-3531","article-title":"Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells","volume":"107","author":"Obeng","year":"2006","journal-title":"Blood"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"8386","DOI":"10.1038\/sj.onc.1207170","article-title":"Proteasome inhibitor PS-341 abrogates IL-6 triggered signaling cascades via caspase-dependent downregulation of gp130 in multiple myeloma","volume":"22","author":"Hideshima","year":"2003","journal-title":"Oncogene"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/onc.2008.385","article-title":"Bortezomib overcomes cell-adhesion-mediated drug resistance through downregulation of VLA-4 expression in multiple myeloma","volume":"28","author":"Kikuchi","year":"2009","journal-title":"Oncogene"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/S1535-6108(04)00120-5","article-title":"The development of proteasome inhibitors as anticancer drugs","volume":"5","author":"Adams","year":"2004","journal-title":"Cancer Cell"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.ccr.2007.07.004","article-title":"Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma","volume":"12","author":"Annunziata","year":"2007","journal-title":"Cancer Cell"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1006\/bbrc.1995.2465","article-title":"Inactivation of NF-kappa B inhibitor I kappa B alpha: Ubiquitin-dependent proteolysis and its degradation product","volume":"215","author":"Li","year":"1995","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1097\/MOH.0b013e328302c7f4","article-title":"NF-kappaB in the pathogenesis and treatment of multiple myeloma","volume":"15","author":"Li","year":"2008","journal-title":"Curr. Opin. Hematol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"3551","DOI":"10.1002\/j.1460-2075.1993.tb06029.x","article-title":"A cooperative interaction between NF-kappa B and Sp1 is required for HIV-1 enhancer activation","volume":"12","author":"Perkins","year":"1993","journal-title":"EMBO J."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"2364","DOI":"10.1182\/blood-2007-08-110171","article-title":"Bortezomib induces DNA hypomethylation and silenced gene transcription by interfering with Sp1\/NF-\u03baB\u2013dependent DNA methyltransferase activity in acute myeloid leukemia","volume":"111","author":"Liu","year":"2008","journal-title":"Blood"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"2377","DOI":"10.1182\/blood-2002-06-1768","article-title":"The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: Therapeutic applications","volume":"101","author":"Mitsiades","year":"2003","journal-title":"Blood"},{"key":"ref_127","doi-asserted-by":"crossref","unstructured":"Velegzhaninov, I.O., Ievlev, V.A., Pylina, Y.I., Shadrin, D.M., and Vakhrusheva, O.M. (2018). Programming of Cell Resistance to Genotoxic and Oxidative Stress. Biomedicines, 6.","DOI":"10.3390\/biomedicines6010005"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"17626","DOI":"10.1038\/s41598-017-17977-9","article-title":"Proteasome stress sensitizes malignant pleural mesothelioma cells to bortezomib-induced apoptosis","volume":"7","author":"Cerruti","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1182\/blood.V98.6.1897","article-title":"Reduction in drug-induced DNA double-strand breaks associated with beta1 integrin-mediated adhesion correlates with drug resistance in U937 cells","volume":"98","author":"Hazlehurst","year":"2001","journal-title":"Blood"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"7429","DOI":"10.1073\/pnas.94.14.7429","article-title":"Cloning and characterization of a mammalian 8-oxoguanine DNA glycosylase","volume":"94","author":"Rosenquist","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_131","doi-asserted-by":"crossref","unstructured":"\u0141uczkowska, K., Rogi\u0144ska, D., Ula\u0144czyk, Z., Paczkowska, E., Schmidt, C.A., and Machali\u0144ski, B. (2020). Molecular Mechanisms of Bortezomib Action: Novel Evidence for the miRNA-mRNA Interaction Involvement. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21010350"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1038\/nrg2504","article-title":"Small silencing RNAs: An expanding universe","volume":"10","author":"Ghildiyal","year":"2009","journal-title":"Nat. Rev. Genet."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"917","DOI":"10.7150\/ijbs.7224","article-title":"The many faces of C\/EBP\u03b4 and their relevance for inflammation and cancer","volume":"9","author":"Balamurugan","year":"2013","journal-title":"Int. J. Biol. Sci."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"e3167","DOI":"10.1038\/cddis.2017.520","article-title":"Bortezomib-induced miRNAs direct epigenetic silencing of locus genes and trigger apoptosis in leukemia","volume":"8","author":"Chu","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"3895","DOI":"10.1182\/blood-2006-08-040147","article-title":"The C\/EBPdelta tumor suppressor is silenced by hypermethylation in acute myeloid leukemia","volume":"109","author":"Agrawal","year":"2007","journal-title":"Blood"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"2623","DOI":"10.1158\/1535-7163.MCT-15-0025","article-title":"HMDB and 5-AzadC Combination Reverses Tumor Suppressor CCAAT\/Enhancer-Binding Protein Delta to Strengthen the Death of Liver Cancer Cells","volume":"14","author":"Li","year":"2015","journal-title":"Mol. Cancer Ther."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1158\/1078-0432.CCR-15-1169","article-title":"Inhibition of the EGFR\/STAT3\/CEBPD Axis Reverses Cisplatin Cross-resistance with Paclitaxel in the Urothelial Carcinoma of the Urinary Bladder","volume":"23","author":"Wang","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_138","doi-asserted-by":"crossref","unstructured":"Ko, J.H., Lee, J.H., Jung, S.H., Lee, S.G., Chinnathambi, A., Alharbi, S.A., Yang, W.M., Um, J.Y., Sethi, G., and Ahn, K.S. (2017). 2,5-Dihydroxyacetophenone Induces Apoptosis of Multiple Myeloma Cells by Regulating the MAPK Activation Pathway. Molecules, 22.","DOI":"10.20944\/preprints201706.0126.v1"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1124\/pr.107.00106","article-title":"Mitogen-activated protein (MAP) kinase\/MAP kinase phosphatase regulation: Roles in cell growth, death, and cancer","volume":"60","author":"Boutros","year":"2008","journal-title":"Pharmacol. Rev."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"N67","DOI":"10.1097\/00003246-200004001-00008","article-title":"MAP kinase pathways activated by stress: The p38 MAPK pathway","volume":"28","author":"Obata","year":"2000","journal-title":"Crit. Care Med."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1002\/jcb.1150","article-title":"26S proteasome inhibition induces apoptosis and limits growth of human pancreatic cancer","volume":"82","author":"Shah","year":"2001","journal-title":"J. Cell Biochem."},{"key":"ref_142","first-page":"3719","article-title":"Lack of multicellular drug resistance observed in human ovarian and prostate carcinoma treated with the proteasome inhibitor PS-341","volume":"6","author":"Frankel","year":"2000","journal-title":"Clin. Cancer Res."},{"key":"ref_143","first-page":"3071","article-title":"The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells","volume":"61","author":"Hideshima","year":"2001","journal-title":"Cancer Res."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1182\/blood-2012-02-407999","article-title":"Cytotoxic effects of bortezomib in myelodysplastic syndrome\/acute myeloid leukemia depend on autophagy-mediated lysosomal degradation of TRAF6 and repression of PSMA1","volume":"120","author":"Fang","year":"2012","journal-title":"Blood"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"21153","DOI":"10.18632\/oncotarget.15503","article-title":"Proteasome inhibition enhances the efficacy of volasertib-induced mitotic arrest in AML in vitro and prolongs survival in vivo","volume":"8","author":"Schnerch","year":"2017","journal-title":"Oncotarget"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1111\/j.1365-2141.2005.05540.x","article-title":"Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma","volume":"129","author":"Jagannath","year":"2005","journal-title":"Br. J. Haematol."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1200\/JCO.2012.41.6180","article-title":"Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma","volume":"31","author":"Schlag","year":"2013","journal-title":"J. Clin. Oncol."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1056\/NEJMoa1606038","article-title":"Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma","volume":"375","author":"Palumbo","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.3324\/haematol.2019.220962","article-title":"Bortezomib with standard chemotherapy for children with acute myeloid leukemia does not improve treatment outcomes: A report from the Children\u2019s Oncology Group","volume":"105","author":"Aplenc","year":"2020","journal-title":"Haematologica"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"3696","DOI":"10.1200\/JCO.2012.46.7068","article-title":"Phase Ib study of panobinostat and bortezomib in relapsed or relapsed and refractory multiple myeloma","volume":"31","author":"Richardson","year":"2013","journal-title":"J. Clin. Oncol."},{"key":"ref_151","doi-asserted-by":"crossref","unstructured":"Pancheri, E., Guglielmi, V., Wilczynski, G.M., Malatesta, M., Tonin, P., Tomelleri, G., Nowis, D., and Vattemi, G. (2020). Non-Hematologic Toxicity of Bortezomib in Multiple Myeloma: The Neuromuscular and Cardiovascular Adverse Effects. Cancers, 12.","DOI":"10.3390\/cancers12092540"},{"key":"ref_152","first-page":"111","article-title":"Peroxisome biogenesis disorders","volume":"1","author":"Argyriou","year":"2016","journal-title":"Transl. Sci. Rare Dis."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.expneurol.2006.11.010","article-title":"Bortezomib-induced peripheral neurotoxicity: A neurophysiological and pathological study in the rat","volume":"204","author":"Cavaletti","year":"2007","journal-title":"Exp. Neurol."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1111\/j.1365-2141.2007.06659.x","article-title":"Unexpected cardiotoxicity in haematological bortezomib treated patients","volume":"138","author":"Enrico","year":"2007","journal-title":"Br. J. Haematol."},{"key":"ref_155","first-page":"20","article-title":"Bortezomib-induced Severe Congestive Heart Failure","volume":"1","author":"Jerkins","year":"2010","journal-title":"Cardiol. Res."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1038\/leu.2011.256","article-title":"Impaired bortezomib binding to mutant \u03b25 subunit of the proteasome is the underlying basis for bortezomib resistance in leukemia cells","volume":"26","author":"Franke","year":"2012","journal-title":"Leukemia"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.bcp.2011.10.009","article-title":"Proteasome-based mechanisms of intrinsic and acquired bortezomib resistance in non-small cell lung cancer","volume":"83","author":"Jansen","year":"2012","journal-title":"Biochem. Pharmacol."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"2489","DOI":"10.1182\/blood-2007-08-104950","article-title":"Molecular basis of bortezomib resistance: Proteasome subunit beta5 (PSMB5) gene mutation and overexpression of PSMB5 protein","volume":"112","author":"Oerlemans","year":"2008","journal-title":"Blood"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1038\/s41375-020-0989-4","article-title":"Bortezomib resistance mutations in PSMB5 determine response to second-generation proteasome inhibitors in multiple myeloma","volume":"35","author":"Allmeroth","year":"2021","journal-title":"Leukemia"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.1056\/NEJMoa1301689","article-title":"Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia","volume":"368","author":"Ley","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"1177271919846454","DOI":"10.1177\/1177271919846454","article-title":"Oncogenic Roles and Inhibitors of DNMT1, DNMT3A, and DNMT3B in Acute Myeloid Leukaemia","volume":"14","author":"Wong","year":"2019","journal-title":"Biomark. Insights"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"127908","DOI":"10.1016\/j.bmcl.2021.127908","article-title":"A novel class of selective non-nucleoside inhibitors of human DNA methyltransferase 3A","volume":"40","author":"Huang","year":"2021","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"3824","DOI":"10.1182\/blood-2011-05-352039","article-title":"Molecular predictors of response to decitabine in advanced chronic myelomonocytic leukemia: A phase 2 trial","volume":"118","author":"Braun","year":"2011","journal-title":"Blood"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.3109\/10428194.2013.855309","article-title":"Lack of association of IDH1, IDH2 and DNMT3A mutations with outcome in older patients with acute myeloid leukemia treated with hypomethylating agents","volume":"55","author":"DiNardo","year":"2014","journal-title":"Leuk. Lymphoma"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1038\/leu.2011.342","article-title":"DNMT3A mutations and response to the hypomethylating agent decitabine in acute myeloid leukemia","volume":"26","author":"Metzeler","year":"2012","journal-title":"Leukemia"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"613","DOI":"10.3324\/haematol.2013.099549","article-title":"Why methylation is not a marker predictive of response to hypomethylating agents","volume":"99","author":"Voso","year":"2014","journal-title":"Haematologica"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"2444","DOI":"10.1016\/j.clinthera.2010.12.003","article-title":"Economic analysis of decitabine versus best supportive care in the treatment of intermediate- and high-risk myelodysplastic syndromes from a US payer perspective","volume":"32","author":"Pan","year":"2010","journal-title":"Clin. Ther."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1080\/15257770.2011.652330","article-title":"Role of human nucleoside transporters in the uptake and cytotoxicity of azacitidine and decitabine","volume":"31","author":"Damaraju","year":"2012","journal-title":"Nucleosides Nucleotides Nucleic Acids"},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1517\/17425255.2012.680885","article-title":"The role of transporters in the toxicity of nucleoside and nucleotide analogs","volume":"8","author":"Koczor","year":"2012","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/S1470-2045(09)70003-8","article-title":"Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: A randomised, open-label, phase III study","volume":"10","author":"Fenaux","year":"2009","journal-title":"Lancet Oncol."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"a018713","DOI":"10.1101\/cshperspect.a018713","article-title":"Erasers of histone acetylation: The histone deacetylase enzymes","volume":"6","author":"Seto","year":"2014","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"5528","DOI":"10.1182\/blood-2018-99-119728","article-title":"Histone Deacetylase Inhibitors in Myelodysplastic Syndrome","volume":"132","author":"Selene","year":"2018","journal-title":"Blood"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"2652","DOI":"10.1182\/blood-2019-125924","article-title":"A Phase 3 Randomized Study (PRIMULA) of the Epigenetic Combination of Pracinostat, a Pan-Histone Deacetylase (HDAC) Inhibitor, with Azacitidine (AZA) in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) Unfit for Standard Intensive Chemotherapy (IC)","volume":"134","author":"Fong","year":"2019","journal-title":"Blood"},{"key":"ref_174","doi-asserted-by":"crossref","unstructured":"Zhuang, L., Ma, Y., Wang, Q., Zhang, J., Zhu, C., Zhang, L., and Xu, X. (2016). Atg3 Overexpression Enhances Bortezomib-Induced Cell Death in SKM-1 Cell. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0158761"},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1158\/1541-7786.MCR-12-0607","article-title":"Epigenetic control of NF-\u03baB-dependent FAS gene transcription during progression of myelodysplastic syndromes","volume":"11","author":"Ettou","year":"2013","journal-title":"Mol. Cancer Res."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"2297","DOI":"10.1038\/leu.2012.152","article-title":"Fas expression at diagnosis as a biomarker of azacitidine activity in high-risk MDS and secondary AML","volume":"26","author":"Ettou","year":"2012","journal-title":"Leukemia"},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1038\/s41598-020-57698-0","article-title":"Silencing of SENP2 in Multiple Myeloma Induces Bortezomib Resistance by Activating NF-\u03baB Through the Modulation of I\u03baB\u03b1 Sumoylation","volume":"10","author":"Xie","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"2827","DOI":"10.1182\/blood-2009-03-211045","article-title":"The sumoylation pathway is dysregulated in multiple myeloma and is associated with adverse patient outcome","volume":"115","author":"Driscoll","year":"2010","journal-title":"Blood"},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"566","DOI":"10.3389\/fonc.2018.00566","article-title":"The Epigenome in Multiple Myeloma: Impact on Tumor Cell Plasticity and Drug Response","volume":"8","author":"Lui","year":"2018","journal-title":"Front. Oncol."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"8567","DOI":"10.1073\/pnas.0503221102","article-title":"Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma","volume":"102","author":"Hideshima","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"2579","DOI":"10.1182\/blood-2011-10-387365","article-title":"Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma","volume":"119","author":"Santo","year":"2012","journal-title":"Blood"},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1111\/bjh.13315","article-title":"Ricolinostat (ACY-1215) induced inhibition of aggresome formation accelerates carfilzomib-induced multiple myeloma cell death","volume":"169","author":"Mishima","year":"2015","journal-title":"Br. J. Haematol."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1182\/blood-2016-08-731240","article-title":"Silencing c-Myc translation as a therapeutic strategy through targeting PI3K\u03b4 and CK1\u03b5 in hematological malignancies","volume":"129","author":"Deng","year":"2017","journal-title":"Blood"},{"key":"ref_184","doi-asserted-by":"crossref","unstructured":"Guo, M., Sun, D., Fan, Z., Yuan, Y., Shao, M., Hou, J., Zhu, Y., Wei, R., Zhu, Y., and Qian, J. (2019). Targeting MK2 Is a Novel Approach to Interfere in Multiple Myeloma. Front. Oncol., 9.","DOI":"10.3389\/fonc.2019.00722"},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s40170-017-0169-9","article-title":"Bortezomib resistance in multiple myeloma is associated with increased serine synthesis","volume":"5","author":"Zaal","year":"2017","journal-title":"Cancer Metab."},{"key":"ref_186","doi-asserted-by":"crossref","unstructured":"Antao, A.M., Tyagi, A., Kim, K.-S., and Ramakrishna, S. (2020). Advances in Deubiquitinating Enzyme Inhibition and Applications in Cancer Therapeutics. Cancers, 12.","DOI":"10.3390\/cancers12061579"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/7\/641\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:25:44Z","timestamp":1760163944000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/7\/641"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,4]]},"references-count":186,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["ph14070641"],"URL":"https:\/\/doi.org\/10.3390\/ph14070641","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,4]]}}}