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Epigenetics

Epigenetic drugs: reprogramming cancer epigenome


--Manuscript Draft--

Manuscript Number: KEPI-2019-0072

Full Title: Epigenetic drugs: reprogramming cancer epigenome

Article Type: Review

Manuscript Classifications: Cancer Therapeutics; Pharmacology

Abstract: Growing evidence suggests that aberrant epigenetic regulation of gene function is
strongly related to the genesis of cancer. Unlike genetic mutations, the ability to
reprogram the epigenetic landscape in the cancer epigenome is one of the most
promising target therapies both in treatment and in reversal of drug resistance.
Epigenetic alterations in cancer development and progression may be the basis for the
individual variation in drug response. Thus, this review focuses on the emerging area
of pharmaco(epi)genomics, highlighting the epigenetic reprogramming during
tumorigenesis and how the epigenetic markers are targeted as a therapy (Epidrugs)
and its clinical implications in cancer treatment.

Author Comments: Faculty of Medicine


Federal University of Ceara
February 24th, 2019

Editor-in-Chief
Epigenetics

Dear Editor:

On behalf of my co-authors I am submitting the enclosed original research article for


publication in Epigenetics, titled “Epigenetic drugs: reprogramming cancer epigenome”.

This review aims to summarize the main results related to the epigenetic modifications
in carcinogenesis and the emerging area of pharmaco(epi)genomics, highlighting the
epigenetic reprogramming during tumorigenesis and how the epigenetic markers are
targeted as a therapy (Epidrugs) and its clinical implications in cancer treatment. The
work also presents figures with a schematic representation of epigenetic modifications
and the current epidrugs approved by FDA, didactically exposing the information and
helping the readers in the understanding of the epigenetic modulation in cancer
treatment.

This manuscript has not been published or presented elsewhere in part or in entirety
and is not under consideration by another journal. We have read and understood your
journal’s policies, and we believe that neither the manuscript nor the study violates any
of these. There are no conflicts of interest to declare.

Thank you for your consideration. I look forward to hearing from you.

Sincerely,
Prof. Dr. Cristiana Libardi Miranda Furtado, PhD
Drug Research and Development Center, Federal University of Ceara,
Coronel Nunes de Melo 1127, 60020-181, Fortaleza, Ceara, Brazil.
Phone: +55 85 98185-4719 / E-mail: clibardim@gmail.com

Order of Authors Secondary Information:

Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation
Manuscript - Epidrugs

1 Title: Epigenetic drugs: reprogramming cancer epigenome

3 Running title: Epidrugs and cancer

5 Cristiana Libardi Miranda Furtado1,*, Maria Claudia dos Santos Luciano1, Renan da Silva Santos1,

6 Gilvan Pessoa Furtado2, Manoel Odorico Moraes1, Claudia Pessoa1.

1
8 Drug Research and Development Center, Federal University of Ceara, Coronel Nunes de Melo 1127,

9 60020-181, Fortaleza, Ceara, Brazil.


2
10 Oswaldo Cruz Foundation, Fiocruz Ceará, Eusébio, 61760-000, Ceara, Brazil

11

12 *Corresponding author: Prof. Dr. Cristiana L. Miranda-Frutado

13 Email: clibardim@gmail.com

14 Drug Research and Development Center; Federal University of Ceara

15 60020-181, Fortaleza, Ceara, Brazil.

16
2

17 Abstract

18 Growing evidence suggests that aberrant epigenetic regulation of gene function is strongly related to

19 the genesis of cancer. Unlike genetic mutations, the ability to reprogram the epigenetic landscape in

20 the cancer epigenome is one of the most promising target therapies both in treatment and in reversal

21 of drug resistance. Epigenetic alterations in cancer development and progression may be the basis for

22 the individual variation in drug response. Thus, this review focuses on the emerging area of

23 pharmaco(epi)genomics, highlighting the epigenetic reprogramming during tumorigenesis and how

24 the epigenetic markers are targeted as a therapy (Epidrugs) and its clinical implications in cancer

25 treatment.

26

27 Key-words: epigenetics, reprogramming, pharmacology, epidrugs, cancer, treatment

28
3

29 Epigenetic mechanism and cancer

30 Epigenetic alterations are the main mechanisms underlying many human diseases, especially

31 growth and developmental disorders, including Beckwith-Wiedemann (BWS) 1, Silver-Russell 2,


3
32 Prader–Willi and Angelman syndromes. Due to the important role in growth-related pathways,

33 epimutations participate in the earliest stages of neoplasia and have been increasingly recognized as a
4,5
34 hallmark of cancer . Cancer is a group of diseases characterized by the deregulation of important

35 pathways that control cell growth and death. Aberrant cell transformation and tumor progression is a

36 complex and intriguing network of interactions, by which genomic and epigenomic mutations with a

37 strong environmental component induces malignancy and tumorigenesis 6.

38 Since first described by WADDINGTON (1942), the epigenetic landscape of cell development,

39 in which the genotype of an organism responds to the environment in a coordinated way and this

40 response can be fixed independent of mutational effects, revolutionized the field of genetics, emerging

41 a post-genomic era. Epigenetic mechanisms modify chromatin structure by conferring a differential

42 gene expression program without changes in the DNA sequence that is stably maintained through cell
8,9
43 growth . The epigenetic mutations in cancer cells change the structure and stability of the genome

44 and have been suggested as a driver mutation (epimutation) in tumor initiation, and together with
10
45 genetic lesions, propagates the process of carcinogenesis . Thereby, the main mechanisms and

46 elements involved in epigenetic alterations are presented and discussed below.

47

48 DNA methylation

49 DNA methylation is the main mechanism and a well-known epigenetic marker, in which the

50 cytosine (C) in a dinucleotide CpG (cytosine-phosphate-guanine) is covalently modified by a methyl

51 group (–CH3) resulting in a “fifth” base in the DNA sequence, the 5-methylcytosine (m5C) 11,12. This
13
52 modification is catalyzed by DNA methyltransferases (DNMTs) (Figure 1A) , and regulates

53 important biological processes in the mammalian genome that includes transcription and post-
4

54 transcriptional processing, chromatin remodeling, genomic imprinting, X-chromosome inactivation

55 and repression of repetitive DNA elements 14,15.

56 The CpG-rich domains in the vertebrate genome, known as CpG islands (CGI), are

57 predominantly nonmethylated, such as in repetitive sequences, transcription sites and promoter

58 regions. On the other hand, the global genome is CG-deficient and consequently highly methylated

59 (hypermethylated), which is important for chromosomal stability 16


. Thus, hypomethylation and

60 hypermethylation can occur at the same time depending on the genomic region and have different

61 effects on the disease phenotype. Global loss of genomic DNA methylation is often found in several

62 types of tumors and is related to genomic instability, DNA damage, and reactivation of transposons
14,17,18
63 and retroviruses . Whereas aberrant CpG island promoter methylation can inactivate tumor

64 suppressor genes or activate proto-oncogenes 19.

65

66 Histone modification

67 Other important elements of epigenetic regulation are histone proteins, a central component of

68 the nucleosome that is responsible for the stable maintenance of repressive chromatin. The nucleosome

69 is composed of strands of DNA wrapped in two copies each of the histones H2A, H2B, H3 and H4 in

70 an octameric core and a linker histone H1. Chromatin is composed of repeating subunits of

71 nucleosomes and have the potential to define the state in which genetic information is structured within

72 a cell. Conformational changes in the chromatin structure confer a particular arrangement of the

73 genome, with a condensed or non-condensed state, that alters and controls gene expression 20.

74 The epigenetic information in the histone core modifies the chromatin structure for
21
75 transcription activation or repression . The histone post-translational modifications refer to the

76 addition of chemical groups to the tails of these nucleosome-forming proteins, in which the most

77 common chemical modifications are methylation and acetylation that occurs generally next to the
22
78 promoter regions and enhancers . These modifications are catalyzed by multiple enzymes (Figure
5

79 2A), such as histone acetyltransferases (HATs), histone deacetylases (HDACs), histone

80 methyltransferases (HMTs) and histone demethylases (HDMs) that can read, write and erase the

81 histone code in the mammalian genome and play an essential role in regulating the accessibility of
23
82 genomic DNA . Also, the phosphorylation, ubiquitination, and other atypical modifications like

83 citrullination, ADP-ribosylation, deamination, formylation, O-GlcNAcylation, propionylation,

84 butyrylation, crotonylation and proline isomerization occur in these proteins 24. Errors in histone post-

85 transcriptional code may alter gene expression patterns and cause human disease due to changes

86 (epimutations) at the chromatin level 25.

87 Aberrant epigenetic histone modifications have been implicated in cancer pathogenesis and
26,27
88 may impact clinical outcomes, especially in the prognosis and invasiveness of cancer . Reduced

89 levels of lysine acetylation (H3K9ac, H3K18ac, and H4K12ac) and lysine (H3K4me2 and H4K20me3)

90 and arginine methylation (H4R3me2) are associated with poor prognosis in breast cancer 26. Also, a

91 lower level of H3K4me2 is a marker of shorter survival, while reduced H3K4me3 expression is
28
92 associated with a better prognosis . These post-translational histone modifications are important

93 events for cellular growth and development, including cell cycle control, replication, DNA damage

94 response, cell signaling and metabolic pathways and gene expression, which may indicate a malignant

95 process and be potentially useful as biomarkers and a therapeutic strategy for cancer treatment 27,29.

96 Non-coding RNA

97 As mentioned, epigenetic elements are versatile and have an important role in cancer

98 development. Among these elements, non-coding RNAs (ncRNA) have received special attention

99 lately, given the discoveries of their participation in several epigenetic mechanisms which control the

100 expression of genes involved in many biological and pathological processes. This control is done at

101 the level of chromatin structure modulation, transcription regulation and post-transcriptional
30
102 modification . In eukaryotic cells, the transcription proportion is greater than protein translation,

103 since approximately 2-3% of the genome encodes for functional proteins whereas 80% transcribes into
6

31,32
104 non-coding RNA , which is strictly related to the complexity of the organism. Apart from the

105 variety of types and expression levels, these RNAs are classified structurally according to length.

106 Based on this, they are divided into short ncRNA (19-31nt), mid-size ncRNA (<200nt) and long

107 ncRNA (>200nt) 33.

108 In addition to DNA methylation and histone modification, ncRNAs have also been implicated

109 in carcinogenesis as oncogenic drivers and/or tumor suppressors in a complex regulatory network.

110 These regulatory elements interact through physical ligation of a target molecule 34, i.e. RNA-DNA

111 interaction such as the lncRNA XIST that modulates the chromatin structure in the X-inactivation
35
112 process ; RNA-RNA interaction to regulate stability or proteins translation; and RNA-protein

113 interaction, the ribonucleoproteins, as the telomerase complex responsible for telomere elongation and

114 maintenance 34.

115 The complex and multifactorial characteristic of carcinogenicity, in which different pathways

116 can be activated or silenced, both for tumor formation and response as to treatment, drive the research

117 to systemic studies, which takes into account the complex networks of interactions and regulations
36
118 existing in the cellular context to explain the biological phenomena present in living organisms .

119 Since cancer is a complex-multifactorial disease, understanding genomic and epigenomic alterations,

120 cell microenvironment and how it can be reprogrammed, combined with an individual information, is

121 the most promising therapeutic strategy for cancer treatment in the personalized medicine and

122 precision oncology era 37.

123

124 Epigenetic reprogramming and drug therapy in cancer

125 The epigenetic landscape in cancer gives to the tumor cell a peculiar phenotype that may trigger

126 the carcinogenesis process, followed by genetic alterations, that propagates the tumorigenesis 19. These

127 alterations make it difficult to understand the malignancy, as well as the prognosis, treatment and
7

128 surveillance, in which the (epi)genetic variation of each cancer type or even in a single patient may be

129 essential for the development of new therapeutic strategies in a precision medicine era 10,38.

130 Unlike genetic mutations, epigenetic alterations are potentially reversible and have great

131 plasticity, in which the epigenome can be reprogrammed 19, providing new and promising therapeutic

132 targets. The epigenetic drugs (epidrugs) act on DNA and chromatin structure, promoting the disruption

133 of transcriptional and post-transcriptional modifications, regulating mainly the enzymes necessary for

134 their establishment and maintenance, reactivating epigenetically silenced tumor-suppressor and DNA
39,40
135 repair genes . Therapeutic strategies involving epidrugs is a growing field of drug discovery by

136 focusing on the cancer epigenome to develop pharmacological compounds which could restore a

137 “normal” epigenetic landscape 39.

138 Due to its role in the modulation of gene expression, epigenetic disruption has a large

139 implication on many physiological and pathological processes resulting in ‘epigenetic diseases’,

140 including cancer, chromosomal instabilities and mental retardation 41. Nevertheless, the possibility of

141 reprogramming the epigenome, changing the cell landscape, has several implications for the treatment

142 of several pathologies. The new concept of epigenetic therapy seems to be the future of medicine,

143 especially for malignancies, since the treatment is strictly linked to the type of tumor and stage of the

144 disease and targeted therapies have broadened the treatment options available to patients 42,43.

145 The epidrugs are chemical compounds that promote the disruption of transcriptional and post-

146 transcriptional modifications, acting especially on the enzymes necessary for the maintenance and

147 establishment of the epigenetic mechanisms. As such, the main strategy of this therapy is focused on

148 the inhibitors of DNMTs and HDACs (Figure 1) 44. These drugs have implications on the regulation

149 and dysregulation of the physiological and pathological processes, since epigenetic modifications

150 control the chronological and spatial gene expression 45, having a great potential to provide molecular

151 biomarkers 41. Studies in vitro have demonstrated that are many implications under regulation of tumor

152 suppressor genes and DNA repair enzymes 46. More recent works show the great potential of using a
8

153 combination of epigenetic drugs in in vitro assays 47,48 and also in the clinic for chemotherapy treatment
49,50
154 . Epigenetic therapy has also been associated with cell differentiation, cell cycle arrest and cell

155 death, energetic metabolism and other cell issues involving a large number of genes and proteins
47,48,51,52
156 . These features play an important role in cancer development and help the understanding of

157 the evolution of some cancer hallmarks including progression, survival and regulation 53.

158 Several epigenetic therapies are currently in use for cancer treatment, many others are in the

159 developmental pipeline from basic science to better understand the mechanism of action, to preclinical

160 and clinical studies. In a Web of Science database search (December 2018) using the terms “epigenetic

161 and study phases” 1900 manuscripts were found, including in vitro (1140 studies), in vivo (931

162 studies), preclinical (465 studies) and clinical studies (133 studies), involving epigenetic compounds

163 and their mechanisms of regulation. The 133 compounds established in several clinical stages (Stages

164 I, II, III and IV) for drug-development. According to the clinicaltrial.org website, the current clinical

165 investigations regarding epigenetics implications for cancer detection, treatment, and prognosis around

166 the world (Figure 2). In addition to these clinical studies in progress, 6 drugs have been approved so

167 far by the United States Food and Drug Administration (FDA) in the field of epidrugs (Table 1).

168 The DNMT inhibitors (DNMTi) are the first epidrug approved by the FDA that block DNA

169 methylation and restore the function of aberrantly silenced 54. These compounds was primarily used to

170 treat myelodysplastic syndrome (MDS) which are cytidine analogs, i.e. azacitidine (vidaza) and

171 decitabine (5-aza- and 5-aza-2'-deoxycytidine, respectively), and they have also been used for other

172 malignancies 55,56 with great implications in hypertension treatment 57 and cardiac arrhythmia 58. The

173 majority of compounds approved by the FDA for cancer treatment are HDAC inhibitors (HDACi),

174 which show promising results in selectivity index and toxicity. Of the four compounds approved, three

175 are hydroxamic acids, including Vorinostat, used for treatment of cutaneous T-cell lymphoma, and

176 Panobinostat and Belinostat, used for treatment of multiple myeloma. Romidepsin is also used to treat
59–61
177 lymphoma . The general feature of an HDACi, such as Vorinostat, is to enable the increase of
9

178 histone acetylation by blocking the catalytic site of these enzymes, which alters dramatically cellular

179 acetylation patterns causing growth arrest and death in a wide range of transformed cells 62.
63
180 Furthermore, new therapies have emerged, including the use of microRNA , multi-drug
64 65
181 combinations and immunotherapy , helping to improve cancer treatment and reducing drug

182 resistance. Many studies have reported a great potential of epidrugs combined with chemotherapy or
47,48 49,50
183 immunotherapy, both in vitro and in clinical studies (Table 2). Combination therapy using

184 epidrugs has shown promising results in vitro with the greatest increase in apoptosis induction as

185 compared to each compound alone 51,52 and in vivo showing tumor growth inhibition in xenograft nude mice.
48
186 .

187

188 ncRNA targets and based therapy

189 Despite the development of new technologies in the field of diagnostic imaging for cancer in

190 the last decade, analyses of tumor tissue by invasive means such as biopsies and punctures are still

191 required 66. The search for new low cost and faster detection parameters is greatly needed. Therefore,

192 the diversified profile of ncRNA in heathy and tumor cells provides a good biomarker for cancer
67
193 prognosis and therapy . The strategies used for research, experimental processes and therapeutics

194 design are based on their expression in tumoral tissue 68.

195 The ncRNA may be a target for inhibitory drugs or, the opposite, when its supplementation can

196 restore endogenous function in cases of downregulation or gene disruption 69. This strategy has been

197 observed when ncRNAs act as tumor suppressors and their lack contributes to the disruption of
68,70
198 important pathways related to carcinogenesis . Despite RNA diversity, microRNAs are the main

199 target in research and clinical applications 71. As an example, the microRNA family MiR-34 is silenced

200 in a wide variety of cancers and seems to regulate important genes related to the control of cell cycle
72,73
201 and proliferation, such as the C-MYC . Synlogic therapeutics, a biopharmaceutical company,

202 synthesized the first microRNA similar to mir-34, MRX34 73. During the MRX34 preclinical phase,
10

203 efficient delivery of miR-34a into bone metastasis and colon cancer to xenograft models using

204 nanocarriers resulted in a significant decreas in tumor size 74,75.

205 The future anticancer miRNA replacement therapy promises several potential advantages. Due

206 to the small size, miRNAs are well suited for cell delivery. In addition, they may associate with the

207 RISC (RNA-induced silencing complex) to modulate transcript translation in the cytoplasm, avoiding

208 the need to move to the cell nucleus 76. Not only miRNA, but an emerging field based on long non-

209 coding RNAs (lncRNAs) have also been implicated as new targets for cancer development arrest.

210 Several lncRNAs work as natural antisense transcripts (NATs) targeting genes of therapeutic interest,

211 as important cis and trans-acting modulators that induces transcriptional silencing 77. A second strategy

212 deals with the use of Antisense Oligonucleotides (ASO), which are short DNA sequences

213 complementary to the RNA of interest. Though ASOs still need to be approved as an anticancer

214 therapy, MALAT-1 ASOs have already shown efficacy in a preclinical mouse MMTV-PyMT breast

215 cancer model, where Malat1 drives tumor growth and metastasis 27.

216 The “oncomir” term is generally used for a miRNA overexpressed in cancer, evidencing a

217 frequent association of many miRNA with tumorigenesis 78. Anti-miR oligonucleotides are capable of

218 binding with the guide strand of miRNAs. They have shown to be a powerful tool to understand

219 microRNA action and potential therapeutic use 79. Multiple miRNA inhibition therapy has also been

220 used. For example, a combination of the chemotherapeutic drug sunitinib at low dosage with anti-

221 miRNA oligonucleotides targeting the overexpressed miR-21, miR-221/222 and miR-10 can achieve

222 a notable synergistic antitumor effect in pancreatic ductal adenocarcinoma cells, thereby indicating

223 that this combinatory approach might be of great importance for therapeutic applications in this disease
80,81
224 .

225

226 Epigenetic drugs and associations with chemo and immunotherapies


11

227 Translational studies aim to bring the results obtained by the scientific community to the

228 clinical experience. The use of epidrugs as chemotherapy in recent clinical studies and approved

229 therapies, alone or in association with other drugs, have shown an improvement in cancer treatment,

230 which includes remission of tumors, drug resistance reduction, increase in life expectancy and a

231 reduction in adverse events 82–84.

232 An important factor that hinders treatment success of traditional chemotherapy is

233 chemoresistance, which is caused by genetic mutations involving different cellular mechanisms such
85
234 as the cell cycle, apoptosis and cell adhesion . Clinical combination therapy has enhanced the
83,84,86
235 treatment of patients with several types of cancer . Further, considering epidrugs in clinical

236 studies, the combinations of Decitabine and Panobinostat with Temozolomide to treat resistant

237 melanoma, presented good responses showing disease stabilization or even a remission of cancer 50.

238 Another study performed by PILI et al. using Vorinostat and Bevacizumab antibody showed relatively

239 high tolerance, increasing the efficacy in the treatment of renal carcinoma (PILI et al., 2017). These

240 therapies seem to be a promising treatment, especially in personalized medicine, however little is

241 known about the clinical effects of these drugs and on which pathways they may be acting. Treatment

242 using Azacitidine, Valproic Acid and carboplatin, each used alone, showed a decrease in tumor size,

243 but the combination of drugs caused high levels of adverse events 82.
87
244 Epigenetic drugs are being tested with promising results in some models of leukemia ,

245 including clinical trials 88,89. The use of epigenetic drugs seems to have the ability to interfere with the

246 functionality of many biological processes 90 and may play a crucial role in progress of multiple drug
83,84,86
247 therapy . However, there is no conclusive evidence on how some epigenetic mechanisms are

248 modulated by these drugs, indicating the necessity of investigations to clarify their mechanism(s) of

249 action 91.

250 Some combinations of traditional chemotherapy and epigenetic drugs have been tested to

251 improve the response and reduce side effects in patients considered age-ineligible for
12

252 chemotherapeutic treatment (GRISHINA et al., 2015). A low-dose of Decitabine was administered

253 alone or in combination with the histone deacetylase inhibitor Valproic Acid and Transretinoic Acid.

254 The study showed the possibility of tolerance for intensive cytotoxic induction and post-remission

255 chemotherapy in these patients. The clinical trial investigation assumes benefit-risk profiles and safety

256 issues when it considers the potential benefit of using epigenetic drugs in combination with decitabine

257 to observe disease control, overall survival, safety, and quality of life in elderly acute myeloid leukemia

258 patients.

259 In addition to traditional chemotherapy, immunotherapy has emerged in recent decades as a

260 potent adjunct to cancer treatment, especially monoclonal antibodies, sometimes used in combination

261 with chemotherapy as first-line treatment for some types of tumors, such as non–small cell lung cancer,

262 breast cancer, colorectal carcinoma and non-Hodgkin’s lymphoma 92,93


. The 2018 Nobel Prize in

263 Physiology or Medicine recognized the significant advance in cancer treatment obtained by

264 immunotherapy and was awarded to James P. Allison and Tasuku Honjo for their discovery of CTLA4

265 and PD1 immune checkpoints, two important targets for therapeutic monoclonal antibodies.

266 Interestingly, recent studies have shown a close relationship between epidrugs and the

267 enhancement of immune checkpoint therapy 94. As mentioned, the actions of the enzymes DNMTs and

268 HDACs are generally associated with transcriptional repression, thereby, the use of epidrugs as

269 DNMTi and HDACi can change the expression of genes involved in immune checkpoint pathways,

270 potentiating the immunotherapy effects 94. Further, drugs that promote epigenetic changes can improve
95
271 antigen presentation by tumor cells, boosting CD8 T-cell killing . In this context, WOODS et al.,

272 (2015) showed that HDACi upregulated PD-1 in melanoma cells in vitro and in a mouse model and

273 when combined with a PD-1–blocking antibody, the treatment decreased tumor progression and

274 improve mice survival. Therefore, several clinical trials have been performed using anti-PD1/PD-L1

275 or anti-CTL4 antibodies in combination with DNMTi or HDACi drugs like Entinostat, Vorinostat, and

276 Azacytidine 97,98. These data bring the hope of more effective treatments for several kinds of tumor.
13

277

278 Conclusions and perspectives

279 While clinical studies have been carried out using large combinations of medicines for cancer

280 treatment, some results are expected from these associations including increased life expectancy and

281 fewer side effects from chemotherapy chemotherapy’s side effects. On the other hand, the scientific

282 community is still attempting to understand the mechanism of action of these drugs when administered

283 alone or in combination. The in vitro assays with translational feedback from clinical reports are great

284 tools to illustrate and understand these mechanisms, associating epigenetic modification with

285 modulation of phenotypes. New therapies have emerged with important breakthroughs in cancer

286 treatment such as gene therapy using virus vectors, antibody-drug conjugates, bispecific antibodies

287 and recently the CAR-T cell technology, approved by FDA in non-Hodgkin lymphoma (NHL) and B-

288 cell acute lymphoblastic leukemia (ALL). Although promising, these therapies are expensive, which

289 impairs the universalization of treatment. Thus, the best understanding of epigenetic changes related

290 to the onset and progression of cancer is essential for the development of more cost-effective and

291 efficient anti-tumor drugs and treatments.

292

293 FUNDING

294 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Programa de Excelência

295 Acadêmica (CAPES-PROEX), Programa de Apoio à Pós-Graduação (CAPES-PROAP).

296

297 ACKNOWLEDGEMENTS

298 The authors are grateful to the members of the Experimental Oncology Laboratory (LOE) at Drug

299 Research and Development Center (NPDM), Federal University of Ceara. We also thank Glen

300 McGugan for the English review of the manuscript.

301 CONFLICT OF INTEREST


14

302 The authors declare that they have no conflict of interest.

303

304 REFERENCES

305 1. Horike S -i. Targeted disruption of the human LIT1 locus defines a putative imprinting control

306 element playing an essential role in Beckwith-Wiedemann syndrome. Hum Mol Genet 2000;

307 2. Eggermann T, Schönherr N, Meyer E, Obermann C, Mavany M, Eggermann K, Ranke MB,

308 Wollmann HA. Epigenetic mutations in 11p15 in Silver-Russell syndrome are restricted to the

309 telomeric imprinting domain. J Med Genet 2006;

310 3. Buiting K. Prader-Willi syndrome and Angelman syndrome. Am. J. Med. Genet. Part C

311 Semin. Med. Genet.2010;

312 4. Murphy SK, Jirtle RL. Imprinting evolution and the price of silence. BioEssays2003;

313 5. Das R, Hampton DD, Jirtle RL. Imprinting evolution and human health. Mamm.

314 Genome2009;

315 6. Werner HMJ, Mills GB, Ram PT. Cancer systems biology: A peek into the future of patient

316 care? Nat. Rev. Clin. Oncol.2014;

317 7. Waddington CH. Canalization of development and the inheritance of acquired characters.

318 Nature 1942;

319 8. Waddington CH. Canalization of development and genetic assimilation of acquired characters.

320 Nature 1959;

321 9. Haig D. The (dual) origin of epigenetics. In: Cold Spring Harbor Symposia on Quantitative

322 Biology. 2004.

323 10. Feinberg AP, Ohlsson R, Henikoff S. The epigenetic progenitor origin of human cancer. Nat

324 Rev Genet 2006; 7:21–33.

325 11. Widschwendter M. 5-Methylcytosine - The fifth base of DNA: The fifth wheel on a car or a

326 highly promising diagnostic and therapeutic target in cancer? Dis Markers 2007;
15

327 12. Geiman TM, Muegge K. DNA methylation in early development. Mol Reprod Dev [Internet]

328 2009 [cited 2018 Sep 8]; 77:n/a-n/a. Available from:

329 http://www.ncbi.nlm.nih.gov/pubmed/19921744

330 13. Bestor TH. The DNA methyltransferases of mammals. Hum Mol Genet 2000;

331 14. Robertson KD. DNA methylation, methyltransferases, and cancer. Oncogene2001;

332 15. Kurihara Y, Kawamura Y, Uchijima Y, Amamo T, Kobayashi H, Asano T, Kurihara H.

333 Maintenance of genomic methylation patterns during preimplantation development requires

334 the somatic form of DNA methyltransferase 1. Dev Biol 2008;

335 16. Deaton A, Bird A. CpG islands and the regulation of transcription. Genes Dev 2011;

336 17. Brothman AR, Swanson G, Maxwell TM, Cui J, Murphy KJ, Herrick J, Speights VO, Isaac J,

337 Rohr LR. Global hypomethylation is common in prostate cancer cells: A quantitative predictor

338 for clinical outcome? Cancer Genet Cytogenet 2005;

339 18. Hon GC, Hawkins RD, Caballero OL, Lo C, Lister R, Pelizzola M, Valsesia A, Ye Z, Kuan S,

340 Edsall LE, et al. Global DNA hypomethylation coupled to repressive chromatin domain

341 formation and gene silencing in breast cancer. Genome Res 2012;

342 19. Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis 2009; 31:27–36.

343 20. Müller O, Kepper N, Schöpflin R, Ettig R, Rippe K, Wedemann G. Changing chromatin fiber

344 conformation by nucleosome repositioning. Biophys J 2014; 107:2141–50.

345 21. Barth TK, Imhof A. Fast signals and slow marks: the dynamics of histone modifications.

346 Trends Biochem. Sci.2010;

347 22. Wang Z, Schones DE, Zhao K. Characterization of human epigenomes. Curr. Opin. Genet.

348 Dev.2009;

349 23. Swygert SG, Peterson CL. Chromatin dynamics: Interplay between remodeling enzymes and

350 histone modifications. Biochim. Biophys. Acta - Gene Regul. Mech.2014; 1839:728–36.

351 24. Tweedie-Cullen RY, Brunner AM, Grossmann J, Mohanna S, Sichau D, Nanni P, Panse C,
16

352 Mansuy IM. Identification of combinatorial patterns of post-translational modifications on

353 individual histones in the mouse brain. PLoS One 2012;

354 25. Dieker J, Muller S. Epigenetic histone code and autoimmunity. Clin. Rev. Allergy

355 Immunol.2010;

356 26. Elsheikh SE, Green AR, Rakha EA, Powe DG, Ahmed RA, Collins HM, Soria D, Garibaldi

357 JM, Paish CE, Ammar AA, et al. Global histone modifications in breast cancer correlate with

358 tumor phenotypes, prognostic factors, and patient outcome. Cancer Res 2009;

359 27. Shanmugam MK, Arfuso F, Arumugam S, Chinnathambi A, Jinsong B, Warrier S, Wang LZ,

360 Kumar AP, Ahn KS, Sethi G, et al. Role of novel histone modifications in cancer. Oncotarget

361 [Internet] 2018 [cited 2018 Sep 8]; 9:11414–26. Available from:

362 http://www.ncbi.nlm.nih.gov/pubmed/29541423

363 28. Li X, Harris CJ, Zhong Z, Chen W, Liu R, Jia B, Wang Z, Li S, Jacobsen SE, Du J.

364 Mechanistic insights into plant SUVH family H3K9 methyltransferases and their binding to

365 context-biased non-CG DNA methylation. Proc Natl Acad Sci 2018;

366 29. Kaypee S, Sudarshan D, Shanmugam MK, Mukherjee D, Sethi G, Kundu TK. Aberrant lysine

367 acetylation in tumorigenesis: Implications in the development of therapeutics. Pharmacol Ther

368 2016;

369 30. Penna I, Gigoni A, Costa D, Vella S, Russo D, Poggi A, Villa F, Brizzolara A, Canale C,

370 Mescola A, et al. The inhibition of 45A ncRNA expression reduces tumor formation, affecting

371 tumor nodules compactness and metastatic potential in neuroblastoma cells. Oncotarget 2017;

372 31. Chen J, Miao Z, Xue B, Shan Y, Weng G, Shen B. Long non-coding RNAs in urologic

373 malignancies: Functional roles and clinical translation. J. Cancer2016;

374 32. Barata P, Sood AK, Hong DS. RNA-targeted therapeutics in cancer clinical trials: Current

375 status and future directions. Cancer Treat. Rev.2016;

376 33. Qi P, Zhou X, Du X. Circulating long non-coding RNAs in cancer: current status and future
17

377 perspectives. Mol Cancer 2016;

378 34. Anastasiadou E, Jacob LS, Slack FJ. Non-coding RNA networks in cancer. Nat. Rev.

379 Cancer2017;

380 35. Mohammad F, Mondal T, Kanduri C. Epigenetics of imprinted long noncoding RNAs.

381 Epigenetics2009;

382 36. Welch GR, Clegg JS. From protoplasmic theory to cellular systems biology: a 150-year

383 reflection. Am J Physiol Physiol [Internet] 2010; 298:C1280–90. Available from:

384 http://www.physiology.org/doi/10.1152/ajpcell.00016.2010

385 37. Bozic I, Reiter JG, Allen B, Antal T, Chatterjee K, Shah P, Moon YS, Yaqubie A, Kelly N, Le

386 DT, et al. Evolutionary dynamics of cancer in response to targeted combination therapy. Elife

387 2013;

388 38. Dugger SA, Platt A, Goldstein DB. Drug development in the era of precision medicine. Nat.

389 Rev. Drug Discov.2018;

390 39. Rodríguez-Paredes M, Esteller M. Cancer epigenetics reaches mainstream oncology. Nat Med

391 [Internet] 2011; 17:330–9. Available from: http://dx.doi.org/10.1038/nm.2305

392 40. Salarinia R, Sahebkar A, Peyvandi M, Reza Mirzaei H, Reza Jaafari M, Matbou Riahi M,

393 Ebrahimnejad H, Sadri Nahand J, Hadjati J, Ostadi Asrami M, et al. Epi-Drugs and Epi-miRs:

394 Moving Beyond Current Cancer Therapies. Curr Cancer Drug Targets 2016;

395 41. Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease and prospects for

396 epigenetic therapy. Nature 2004; 429:457–63.

397 42. Mund C, Lyko F. Epigenetic cancer therapy: Proof of concept and remaining challenges.

398 BioEssays2010;

399 43. Jones PA, Issa JPJ, Baylin S. Targeting the cancer epigenome for therapy. Nat. Rev.

400 Genet.2016;

401 44. Rodríguez-Paredes M, Esteller M. Cancer epigenetics reaches mainstream oncology. Nat.
18

402 Med.2011;

403 45. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat. Rev.

404 Genet.2002; 3:415–28.

405 46. Alcazar O, Achberger S, Aldrich W, Hu Z, Negrotto S, Saunthararajah Y, Triozzi P.

406 Epigenetic regulation by decitabine of melanoma differentiation in vitro and in vivo. Int J

407 Cancer 2012; 131:18–29.

408 47. Hsu CC, Chang WC, Hsu TI, Liu JJ, Yeh SH, Wang JY, Liou JP, Ko CY, Chang KY, Chuang

409 JY. Suberoylanilide hydroxamic acid represses glioma stem-like cells. J Biomed Sci [Internet]

410 2016; 23:1–12. Available from: http://dx.doi.org/10.1186/s12929-016-0296-6

411 48. Pan C-H, Chang Y-F, Lee M-S, Wen B-C, Ko J-C, Liang S-K, Liang M-C. Vorinostat

412 enhances the cisplatin-mediated anticancer effects in small cell lung cancer cells. BMC

413 Cancer [Internet] 2016; 16:857. Available from:

414 http://bmccancer.biomedcentral.com/articles/10.1186/s12885-016-2888-7

415 49. Voso MT, Santini V, Finelli C, Musto P, Pogliani E, Angelucci E, Fioritoni G, Alimena G,

416 Maurillo L, Cortelezzi A, et al. Valproic acid at therapeutic plasma levels may increase 5-

417 azacytidine efficacy in higher risk myelodysplastic syndromes. Clin Cancer Res 2009;

418 15:5002–7.

419 50. Xia C, Leon-Ferre R, Laux D, Deutsch J, Smith BJ, Frees M, Milhem M. Treatment of

420 resistant metastatic melanoma using sequential epigenetic therapy (decitabine and

421 panobinostat) combined with chemotherapy (temozolomide). Cancer Chemother Pharmacol

422 2014; 74:691–7.

423 51. Wasim L, Chopra M. Panobinostat induces apoptosis via production of reactive oxygen

424 species and synergizes with topoisomerase inhibitors in cervical cancer cells. Biomed

425 Pharmacother [Internet] 2016; 84:1393–405. Available from:

426 http://dx.doi.org/10.1016/j.biopha.2016.10.057
19

427 52. Staberg M, Michaelsen SR, Rasmussen RD, Villingshøj M, Poulsen HS, Hamerlik P.

428 Inhibition of histone deacetylases sensitizes glioblastoma cells to lomustine. Cell Oncol

429 [Internet] 2017; 40:21–32. Available from: http://dx.doi.org/10.1007/s13402-016-0301-9

430 53. Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell2011; 144:646–74.

431 54. Kaminskas E, Farrell AT, Wang Y-C, Sridhara R, Pazdur R. FDA drug approval summary:

432 azacitidine (5-azacytidine, Vidaza) for injectable suspension. Oncologist [Internet] 2005 [cited

433 2018 Sep 8]; 10:176–82. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15793220

434 55. Matsui T, Sakamoto N, Doi A, Fujii T, Ohno N, Sahara N, Irie S. [Azacitidine for Therapy-

435 Related Myelodysplastic Syndrome Following Oxaliplatin (L-OHP)Therapy for Metastatic

436 Rectal Cancer]. Gan To Kagaku Ryoho [Internet] 2018 [cited 2018 Sep 8]; 45:1201–3.

437 Available from: http://www.ncbi.nlm.nih.gov/pubmed/30158420

438 56. Laille E, Savona MR, Scott BL, Boyd TE, Dong Q, Skikne B. Pharmacokinetics of different

439 formulations of oral azacitidine (CC-486) and the effect of food and modified gastric pH on

440 pharmacokinetics in subjects with hematologic malignancies. J Clin Pharmacol [Internet]

441 2014 [cited 2018 Sep 8]; 54:630–9. Available from: http://doi.wiley.com/10.1002/jcph.251

442 57. Watson CJ, Horgan S, Neary R, Glezeva N, Tea I, Corrigan N, McDonald K, Ledwidge M,

443 Baugh J. Epigenetic Therapy for the Treatment of Hypertension-Induced Cardiac Hypertrophy

444 and Fibrosis. J Cardiovasc Pharmacol Ther [Internet] 2016 [cited 2018 Sep 8]; 21:127–37.

445 Available from: http://journals.sagepub.com/doi/10.1177/1074248415591698

446 58. Doñate Puertas R, Meugnier E, Romestaing C, Rey C, Morel E, Lachuer J, Gadot N, Scridon

447 A, Julien C, Tronc F, et al. Atrial fibrillation is associated with hypermethylation in human

448 left atrium, and treatment with decitabine reduces atrial tachyarrhythmias in spontaneously

449 hypertensive rats. Transl Res [Internet] 2017 [cited 2018 Sep 8]; 184:57–67.e5. Available

450 from: http://www.ncbi.nlm.nih.gov/pubmed/28427903

451 59. Yazbeck VY, Grant S. Romidepsin for the treatment of non-Hodgkin’s lymphoma. Expert
20

452 Opin Investig Drugs [Internet] 2015 [cited 2018 Sep 8]; 24:965–79. Available from:

453 https://www.tandfonline.com/doi/full/10.1517/13543784.2015.1041586

454 60. Iyer SP, Foss FF. Romidepsin for the Treatment of Peripheral T-Cell Lymphoma. Oncologist

455 [Internet] 2015 [cited 2018 Sep 8]; 20:1084–91. Available from:

456 http://www.ncbi.nlm.nih.gov/pubmed/26099743

457 61. Coiffier B, Pro B, Prince HM, Foss F, Sokol L, Greenwood M, Caballero D, Morschhauser F,

458 Wilhelm M, Pinter-Brown L, et al. Romidepsin for the treatment of relapsed/refractory

459 peripheral T-cell lymphoma: pivotal study update demonstrates durable responses. J Hematol

460 Oncol [Internet] 2014 [cited 2018 Sep 8]; 7:11. Available from:

461 http://www.ncbi.nlm.nih.gov/pubmed/24456586

462 62. Richon VM, Garcia-Vargas J, Hardwick JS. Development of vorinostat: current applications

463 and future perspectives for cancer therapy. Cancer Lett 2009; 280:201–10.

464 63. Garofalo M, Croce CM. MicroRNAs as therapeutic targets in chemoresistance. Drug Resist

465 Updat 2013;

466 64. Glasgow MDK, Chougule MB. Recent Developments in Active Tumor Targeted

467 Multifunctional Nanoparticles for Combination Chemotherapy in Cancer Treatment and

468 Imaging. J Biomed Nanotechnol [Internet] 2015 [cited 2018 Sep 8]; 11:1859–98. Available

469 from: http://www.ncbi.nlm.nih.gov/pubmed/26554150

470 65. Crea F, Nobili S, Paolicchi E, Perrone G, Napoli C, Landini I, Danesi R, Mini E. Epigenetics

471 and chemoresistance in colorectal cancer: An opportunity for treatment tailoring and novel

472 therapeutic strategies. Drug Resist Updat 2011;

473 66. Sauter ER. Reliable Biomarkers to Identify New and Recurrent Cancer. Eur J breast Heal

474 [Internet] 2017 [cited 2018 Sep 8]; 13:162–7. Available from:

475 http://www.ncbi.nlm.nih.gov/pubmed/29082372

476 67. Rasool M, Malik A, Zahid S, Basit Ashraf MA, Qazi MH, Asif M, Zaheer A, Arshad M, Raza
21

477 A, Jamal MS. Non-coding RNAs in cancer diagnosis and therapy. Non-coding RNA Res

478 2016;

479 68. Inamura K. Major Tumor Suppressor and Oncogenic Non-Coding RNAs: Clinical Relevance

480 in Lung Cancer. Cells 2017;

481 69. Vitiello M, Tuccoli A, Poliseno L. Long non-coding RNAs in cancer: implications for

482 personalized therapy. Cell Oncol (Dordr) 2014;

483 70. Shao Q, Xu J, Deng R, Wei W, Zhou B, Yue C, Zhu M, Huang X, Zhu H. Long non-coding

484 RNA-422 acts as a tumor suppressor in colorectal cancer. Biochem Biophys Res Commun

485 [Internet] 2018 [cited 2018 Sep 8]; 495:539–45. Available from:

486 https://www.sciencedirect.com/science/article/pii/S0006291X17320545?via%3Dihub

487 71. Ji W, Sun B, Su C. Targeting microRNAs in cancer gene therapy. Genes (Basel).2017;

488 72. Hosseinahli N, Aghapour M, Duijf PHG, Baradaran B. Treating cancer with microRNA

489 replacement therapy: A literature review. J. Cell. Physiol.2018;

490 73. Farooqi AA, Tabassum S, Ahmad A. MicroRNA-34a: A versatile regulator of myriads of

491 targets in different cancers. Int. J. Mol. Sci.2017;

492 74. Gaur S, Wen Y, Song JH, Parikh NU, Mangala LS, Blessing AM, Ivan C, Wu SY, Varkaris A,

493 Shi Y, et al. Chitosan nanoparticle-mediated delivery of miRNA-34a decreases prostate tumor

494 growth in the bone and its expression induces non-canonical autophagy. Oncotarget 2015;

495 75. Tazawa H, Tsuchiya N, Izumiya M, Nakagama H. Tumor-suppressive miR-34a induces

496 senescence-like growth arrest through modulation of the E2F pathway in human colon cancer

497 cells. Proc Natl Acad Sci 2007;

498 76. Shah MY, Ferrajoli A, Sood AK, Lopez-Berestein G, Calin GA. microRNA Therapeutics in

499 Cancer — An Emerging Concept. EBioMedicine2016;

500 77. Renganathan A, Felley-Bosco E. Long Noncoding RNAs in Cancer and Therapeutic Potential

501 [Internet]. In: Advances in experimental medicine and biology. 2017 [cited 2018 Sep 8]. page
22

502 199–222.Available from: http://www.ncbi.nlm.nih.gov/pubmed/28815541

503 78. Svoronos AA, Engelman DM, Slack FJ. OncomiR or tumor suppressor? The duplicity of

504 MicroRNAs in cancer. Cancer Res.2016;

505 79. Jahanafrooz Z, Motamed N, Bakhshandeh B. Effects of miR-21 downregulation and silibinin

506 treatment in breast cancer cell lines. Cytotechnology [Internet] 2017 [cited 2018 Sep 8];

507 69:667–80. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28321778

508 80. Song J, Ouyang Y, Che J, Li X, Zhao Y, Yang K, Zhao X, Chen Y, Fan C, Yuan W. Potential

509 Value of miR-221/222 as Diagnostic, Prognostic, and Therapeutic Biomarkers for Diseases.

510 Front Immunol [Internet] 2017 [cited 2018 Sep 8]; 8:56. Available from:

511 http://www.ncbi.nlm.nih.gov/pubmed/28261196

512 81. Fan M, Li X, Jiang W, Huang Y, Li J, Wang Z. A long non-coding RNA, PTCSC3, as a tumor

513 suppressor and a target of miRNAs in thyroid cancer cells. Exp Ther Med 2013;

514 82. Falchook GS, Fu S, Naing A, Hong DS, Hu W, Moulder S, Wheler JJ, Sood AK, Bustinza-

515 Linares E, Parkhurst KL, et al. Methylation and histone deacetylase inhibition in combination

516 with platinum treatment in patients with advanced malignancies. Invest New Drugs 2013;

517 31:1192–200.

518 83. Pili R, Liu G, Chintala S, Verheul H, Rehman S, Attwood K, Lodge MA, Wahl R, Martin JI,

519 Miles KM, et al. Combination of the histone deacetylase inhibitor vorinostat with

520 bevacizumab in patients with clear-cell renal cell carcinoma: A multicentre, single-arm phase

521 I/II clinical trial. Br J Cancer [Internet] 2017; 116:874–83. Available from:

522 http://dx.doi.org/10.1038/bjc.2017.33

523 84. Shah K, Mirza S, Desai U, Jain N, Rawal R. Synergism of Curcumin and Cytarabine in the

524 down regulation of Multi Drug Resistance Genes in Acute Mieloyd Leukemia. Anti-cancer

525 Agents Med Chem [Internet] 2015; :128–35. Available from:

526 http://www.ncbi.nlm.nih.gov/pubmed/26278546
23

527 85. Alimbetov D, Askarova S, Umbayev B, Davis T, Kipling D. Pharmacological Targeting of

528 Cell Cycle, Apoptotic and Cell Adhesion Signaling Pathways Implicated in Chemoresistance

529 of Cancer Cells. Int J Mol Sci [Internet] 2018 [cited 2018 Dec 12]; 19. Available from:

530 http://www.ncbi.nlm.nih.gov/pubmed/29882812

531 86. Momparler RL, Idaghdour Y, Marquez VE, Momparler LF. Synergistic antileukemic action of

532 a combination of inhibitors of DNA methylation and histone methylation. Leuk Res [Internet]

533 2012; 36:1049–54. Available from: http://dx.doi.org/10.1016/j.leukres.2012.03.001

534 87. Liu Z, ding K, Li L, Liu H, Wang Y, Liu C, Fu R. A novel histone deacetylase inhibitor

535 Chidamide induces G0/G1 arrest and apoptosis in myelodysplastic syndromes. Biomed

536 Pharmacother [Internet] 2016; 83:1032–7. Available from:

537 http://dx.doi.org/10.1016/j.biopha.2016.08.023

538 88. Grishina O, Schmoor C, Döhner K, Hackanson B, Lubrich B, May AM, Cieslik C, Müller MJ,

539 Lübbert M. DECIDER: prospective randomized multicenter phase II trial of low-dose

540 decitabine (DAC) administered alone or in combination with the histone deacetylase inhibitor

541 valproic acid (VPA) and all-trans retinoic acid (ATRA) in patients &gt;60 years with acute .

542 BMC Cancer [Internet] 2015; 15:430. Available from:

543 http://bmccancer.biomedcentral.com/articles/10.1186/s12885-015-1432-5

544 89. Kim E, Ilagan JO, Liang Y, Daubner GM, Stanley C, Ramakrishnan A, Li Y, Chung YR,

545 Micol J, Murphy M, et al. HHS Public Access. 2016; 27:617–30.

546 90. Prachayasittikul V, Prathipati P, Pratiwi R, Phanus-umporn C, Malik AA, Schaduangrat N,

547 Seenprachawong K, Wongchitrat P, Supokawej A, Prachayasittikul V, et al. Exploring the

548 epigenetic drug discovery landscape. Expert Opin Drug Discov [Internet] 2017; 12:345–62.

549 Available from: http://dx.doi.org/10.1080/17460441.2017.1295954

550 91. Yang AS, Yang BJ. The failure of epigenetic combination therapy for cancer and what it

551 might be telling us about DNA methylation inhibitors. Epigenomics 2016; 8:9–12.
24

552 92. Jakovljevic M, Gutzwiller F, Schwenkglenks M, Milovanovic O, Rancic N, Varjacic M,

553 Stojadinovic D, Dagovic A, Matter-Walstra K. Costs differences among monoclonal

554 antibodies-based first-line oncology cancer protocols for breast cancer, colorectal carcinoma

555 and non-Hodgkin’s lymphoma. J BUON 2014; 19:1111–20.

556 93. Karachaliou N, Fernandez-Bruno M, Rosell R. Strategies for first-line immunotherapy in

557 squamous cell lung cancer: Are combinations a game changer? Transl Lung Cancer Res 2018;

558 7:S198–201.

559 94. Chiappinelli KB, Zahnow CA, Ahuja N, Bylin SB. Combining epigenetic and immunotherapy

560 to combat cancer. Cancer Res 2016; 76:1683–9.

561 95. Gallagher SJ, Shklovskaya E, Hersey P. Epigenetic modulation in cancer immunotherapy.

562 Curr Opin Pharmacol [Internet] 2017; 35:48–56. Available from:

563 http://dx.doi.org/10.1016/j.coph.2017.05.006

564 96. Woods DM, Sodre AL, Villagra A, Sarnaik A, Sotomayor EM, Weber J. HDAC Inhibition

565 Upregulates PD-1 Ligands in Melanoma and Augments Immunotherapy with PD-1 Blockade.

566 Cancer Immunol Res [Internet] 2015; 3:1375–85. Available from:

567 http://cancerimmunolres.aacrjournals.org/cgi/doi/10.1158/2326-6066.CIR-15-0077-T

568 97. Dunn J, Rao S. Epigenetics and immunotherapy: The current state of play. Mol Immunol

569 2017; 87:227–39.

570 98. Mazzone R, Zwergel C, Mai A, Valente S. Epi-drugs in combination with immunotherapy: a

571 new avenue to improve anticancer efficacy. Clin Epigenetics 2017; 9:1–15.

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581
582 TABLES
583
584 Table 1 – Epigenetic compounds FDA approved by year, treatment indication and epigenetic target.
Approved Mechanism of
Drug Treatment
(year) action
Azacitidine+
DNA
decitabine or Acute myeloid leukemia
2018 metiltransferase
low-dose cytarabine (AML)
Inhibitor
(VENCLEXTA)

Panobinostat +
Bortezomib + Deacetylase inhibitor
2015 Multiple myeloma
Dexamethasone (iHDAC)
(FARYDAK)
Belinostat Peripheral T Cells Deacetylase inhibitor
2014
(BELODAQ) Lymphoma (iHDAC)
Antidepressive Deacetylase inhibitor
2010 Valproic Acid
Neurologic disorders (iHDAC)
Romidepsin Deacetylase inhibitor
2009 Cutaneous T-cell lymphoma
(IXODAX) (iHDAC)
DNA
5 Azacitidine
2009 Myelodysplastic syndrome metiltransferase
(VIDAZA)
Inhibitor
Vorinostat Deacetylase inhibitor
2006 Cutaneous T-cell lymphoma
(ZOLINZA) (iHDAC)
585

586
26

587 Table 2. In vitro effect of epigenetic drugs associations under different cell lines.

588

589

590
CELL ARRESTED PROTEIN AND
DRUG/COMPOUND FINDINGS REFERENCE
LINES CELL CYCLE PATHWAYS 591
H3 histone
In vivo study showed a significant 592
Vorinostat/Etoposide/ H209 Aceltil alfa-tubulina 48
G0/G1 and S inhibition of tumor growth in xenograft
Cisplatin H143 Thymidylate synthase 593
nude mice
PARP
594
pChk1
Chk1 595
G0/G1 Chk2 The combined treatment showed a 596
Trichostatin A/ 52
U87MG S and G2/M Chk2 higher efficacy compared to the drugs
Lomustine ( ccnu) 597
Caspase-3 alone.
PARP 598
H3 histone
H3 histone The study exhibits synergistic effect of
Pabinostat +
Hela Bcl-xL Pabinostat with topotecan and 51
topoisomerase G0/G1
SiHa p21 etoposide, in a schedule dependent
inhibitors
Caspase-9 manner and enhanced cell death
27

599 FIGURE LEGENDS

600

601 Figure 1. Schematic representation of epigenetic modifications and epidrugs action. (A) The

602 modification of cytosine to 5-methylcytosine (5meC) DNA methylation is catalyzed by DNA

603 methyltransferases (DNMTs). DNMTs requires S-Adenosylmethionine (SAM) as a cofactor for

604 methyl group donation that is converted to S-adenosylhomocysteine (SAH). DNA methylation at a

605 promoter region is related to transcriptional silencing. The DNMTs inhibitors block DNA

606 methylation and restore the function of aberrantly silenced. (B) Histone post-translational acetylation

607 is catalyzed by histone acetyltransferases (HATs) and histone deacetylases (HDACs) into amino acid

608 residues (such as lysine) at histone tails. Histone acetylation is associated with transcription

609 activation and HDACs inhibitors can change the expression of important genes involved in

610 carcinogenesis.

611

612 Figure 2. Progress of epigenetic drugs on different stages of pharmacological studies. (A) Number of

613 epigenetic studies performed into clinical stages, in vitro, in vivo, preclinical and clinical following

614 web of science cover and successful results as single and polichemyotherapy under FDA approvell.

615 (B) A clinical distribution map of epigenetic drugs studies around world following the

616 clinicaltrial.org (December, 2018).

617

618
Table 1

Table 1 – Epigenetic compounds FDA approved by year, treatment indication and epigenetic
target.

Approved Mechanism of
Drug Treatment
(year) action
Azacitidine+
DNA
decitabine or Acute myeloid leukemia
2018 metiltransferase
low-dose cytarabine (AML)
Inhibitor
(VENCLEXTA)

Panobinostat +
Bortezomib + Deacetylase inhibitor
2015 Multiple myeloma
Dexamethasone (iHDAC)
(FARYDAK)
Belinostat Peripheral T Cells Deacetylase inhibitor
2014
(BELODAQ) Lymphoma (iHDAC)
Antidepressive Deacetylase inhibitor
2010 Valproic Acid
Neurologic disorders (iHDAC)
Romidepsin Deacetylase inhibitor
2009 Cutaneous T-cell lymphoma
(IXODAX) (iHDAC)
DNA
5 Azacitidine
2009 Myelodysplastic syndrome metiltransferase
(VIDAZA)
Inhibitor
Vorinostat Deacetylase inhibitor
2006 Cutaneous T-cell lymphoma
(ZOLINZA) (iHDAC)
Table 2

Table 2. In vitro effect of epigenetic drugs associations under different cell lines.

CELL ARRESTED PROTEIN AND


DRUG/COMPOUND FINDINGS REFERENCE
LINES CELL CYCLE PATHWAYS
H3 histone
In vivo study showed a significant
Vorinostat/Etoposide/ H209 Aceltil alfa-tubulina 48
G0/G1 and S inhibition of tumor growth in xenograft
Cisplatin H143 Thymidylate synthase
nude mice
PARP
pChk1
Chk1
G0/G1 Chk2 The combined treatment showed a
Trichostatin A/ 52
U87MG S and G2/M Chk2 higher efficacy compared to the drugs
Lomustine ( ccnu)
Caspase-3 alone.
PARP
H3 histone
H3 histone The study exhibits synergistic effect of
Pabinostat +
Hela Bcl-xL Pabinostat with topotecan and 51
topoisomerase G0/G1
SiHa p21 etoposide, in a schedule dependent
inhibitors
Caspase-9 manner and enhanced cell death
Figure 1 Click here to download Figure Figure 1.tiff
Figure 2 Click here to download Figure Figure 2.tiff

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