Dataset Information

Epigenetic Anti-Cancer Treatment With a Stabilized Carbocyclic Decitabine Analogue.

ABSTRACT: 5-Aza-2'-deoxycytidine (Decitabine, AzadC) is a nucleoside analogue, which is in clinical use to treat patients with myelodysplastic syndrome or acute myeloid leukemia. Its mode of action is unusual because the compound is one of the few drugs that act at the epigenetic level of the genetic code. AzadC is incorporated as an antimetabolite into the genome and creates covalent, inhibitory links to DNA methyltransferases (DNMTs) that methylate 2'-deoxycytidine (dC) to 5-methyl-dC (mdC). Consequently, AzadC treatment leads to a global loss of mdC, which presumably results in a reactivation of silenced genes, among them tumor suppressor and DNA damage response genes. Because AzadC suffers from severe instability, which limits its use in the clinic, a more sophisticated AzadC derivative would be highly valuable. Here, we report that a recently developed carbocyclic AzadC analogue (cAzadC) blocks DNMT1 in the AML cell line MOLM-13 as efficient as AzadC. Moreover, cAzadC has a surprisingly strong anti-proliferative effect and leads to a significantly higher number of double strand breaks compared to AzadC, while showing less off-target toxicity. These results show that cAzadC triggers more deleterious repair and apoptotic pathways in cancer cells than AzadC, which makes cAzadC a promising next generation epigenetic drug.

SUBMITTER: Traube FR

PROVIDER: S-EPMC9314125 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Epigenetic Anti-Cancer Treatment With a Stabilized Carbocyclic Decitabine Analogue.

Traube Franziska R FR Brás Natércia F NF Roos Wynand P WP Sommermann Corinna C CC Diehl Tamara T Mayer Robert J RJ Ofial Armin R AR Müller Markus M Zipse Hendrik H Carell Thomas T

Chemistry (Weinheim an der Bergstrasse, Germany) 20220325 26

5-Aza-2'-deoxycytidine (Decitabine, AzadC) is a nucleoside analogue, which is in clinical use to treat patients with myelodysplastic syndrome or acute myeloid leukemia. Its mode of action is unusual because the compound is one of the few drugs that act at the epigenetic level of the genetic code. AzadC is incorporated as an antimetabolite into the genome and creates covalent, inhibitory links to DNA methyltransferases (DNMTs) that methylate 2'-deoxycytidine (dC) to 5-methyl-dC (mdC). Consequentl ...[more]

PMID: 35285586

Similar Datasets

Project description:BackgroundAberrant epigenetic silencing of tumor suppressor genes has been recognized as a driving force in cancer. Epigenetic drugs such as the DNA methylation inhibitor decitabine reactivate genes and are effective in myeloid leukemia, but resistance often develops and efficacy in solid tumors is limited. To improve their clinical efficacy, we searched among approved anti-cancer drugs for an epigenetic synergistic combination with decitabine.ResultsWe used the YB5 cell line, a clonal derivative of the SW48 colon cancer cell line that contains a single copy of a hypermethylated cytomegalovirus (CMV) promoter driving green fluorescent protein (GFP) to screen for drug-induced gene reactivation and synergy with decitabine. None of the 16 anti-cancer drugs tested had effects on their own. However, in combination with decitabine, platinum compounds showed striking synergy in activating GFP. This was dose dependent, observed both in concurrent and sequential combinations, and also seen with other alkylating agents. Clinically achievable concentrations of carboplatin at (25 μM) and decitabine reactivated GFP in 28 % of the YB5 cells as compared to 15 % with decitabine alone. Epigenetic synergy was also seen at endogenously hypermethylated tumor suppressor genes such as MLH1 and PDLIM4. Genome-wide studies showed that reactivation of hypermethylated genes by the combination was significantly better than that induced by decitabine alone or carboplatin alone. Platinum compounds did not enhance decitabine-induced hypomethylation. Rather, we found significantly inhibited HP1α expression by carboplatin and the combination. This was accompanied by increased histone H3 lysine 4 (H3K4) trimethylation and histone H3 lysine 9 (H3K9) acetylation at reactivated genes (P < 0.0001) and reduced occupancy by methyl-binding proteins including MeCP2 and methyl-CpG-binding domain protein 2 (MBD2) (P < 0.0001).ConclusionsOur results suggest that the combination of decitabine with platinum analogs shows epigenetic synergy that might be exploited in the treatment of different cancers.

Project description:PurposeTo explore the safety and tolerability of combining two epigenetic drugs: decitabine (a DNA methyltransferase inhibitor) and panobinostat (a histone deacetylase inhibitor), with chemotherapy with temozolomide (an alkylating agent). The purpose of such combination is to evaluate the use of epigenetic priming to overcome resistance of melanoma to chemotherapy.MethodsA Phase I clinical trial enrolling patients aged 18 years or older, with recurrent or unresectable stage III or IV melanoma of any site. This trial was conducted with full Institutional Review Board approval and was registered with the National Institutes of Health under the clinicaltrials.gov identifier NCT00925132. Patients were treated with subcutaneous decitabine 0.1 or 0.2 mg/kg three times weekly for 2 weeks (starting on day 1), in combination with oral panobinostat 10, 20, or 30 mg every 96 h (starting on day 8), and oral temozolomide 150 mg/m(2)/day on days 9 through 13. In cycle 2, temozolomide was increased to 200 mg/m(2)/day if neutropenia or thrombocytopenia had not occurred. Each cycle lasted 6 weeks, and patients could receive up to six cycles. Patients who did not demonstrate disease progression were eligible to enter a maintenance protocol with combination of weekly panobinostat and thrice-weekly decitabine until tumor progression, unacceptable toxicity, or withdrawal of consent.ResultsTwenty patients were initially enrolled, with 17 receiving treatment. The median age was 56 years. Eleven (65%) were male, and 6 (35%) were female. Eleven (64.7%) had cutaneous melanoma, 4 (23.5%) had ocular melanoma, and 2 (11.8%) had mucosal melanoma. All patients received at least one treatment cycle and were evaluable for toxicity. Patients received a median of two 6-week treatment cycles (range 1-6). None of the patients experienced DLT. MTD was not reached. Adverse events attributed to treatment included grade 3 lymphopenia (24%), anemia (12%), neutropenia (12%), and fatigue (12%), as well as grade 2 leukopenia (30%), neutropenia (23%), nausea (23%), and lymphopenia (18%). The most common reason for study discontinuation was disease progression.ConclusionsThis triple agent of dual epigenetic therapy in combination with traditional chemotherapy was generally well tolerated by the cohort and appeared safe to be continued in a Phase II trial. No DLTs were observed, and MTD was not reached.

Project description:Despite recent advances in the treatment of human colon cancer, the chemotherapy efficacy against colon cancer is still unsatisfactory. In the present study, effects of concomitant inhibition of the epidermal growth factor receptor (EGFR) and DNA methyltransferase were examined in human colon cancer cells. We demonstrated that decitabine (a DNA methyltransferase inhibitor) synergized with gefitinib (an EGFR inhibitor) to reduce cell viability and colony formation in SW1116 and LOVO cells. However, the combination of the two compounds displayed minimal toxicity to NCM460 cells, a normal human colon mucosal epithelial cell line. The combination was also more effective at inhibiting the AKT/mTOR/S6 kinase pathway. In addition, the combination of decitabine with gefitinib markedly inhibited colon cancer cell migration. Furthermore, gefitinib synergistically enhanced decitabine-induced cytotoxicity was primarily due to apoptosis as shown by Annexin V labeling that was attenuated by z-VAD-fmk, a pan caspase inhibitor. Concomitantly, cell apoptosis resulting from the co-treatment of gefitinib and decitabine was accompanied by induction of BAX, cleaved caspase 3 and cleaved PARP, along with reduction of Bcl-2 compared to treatment with either drug alone. Interestingly, combined treatment with these two drugs increased the expression of XIAP-associated factor 1 (XAF1) which play an important role in cell apoptosis. Moreover, small interfering RNA (siRNA) depletion of XAF1 significantly attenuated colon cancer cells apoptosis induced by the combination of the two drugs. Our findings suggested that gefitinib in combination with decitabine exerted enhanced cell apoptosis in colon cancer cells were involved in mitochondrial-mediated pathway and induction of XAF1 expression. In conclusion, based on the observations from our study, we suggested that the combined administration of these two drugs might be considered as a novel therapeutic regimen for treating colon cancer.

Project description:BackgroundDeoxyribonucleic acid (DNA) methyltransferase inhibitors, such as decitabine, have made great advances in cancer therapy as combinational drugs. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has an obvious anti-tumor effect; however, some gastric cancer (GC) cells are resistant to TRAIL-induced cell death. This study sought to explore the synergistic anti-tumor effect of TRAIL and decitabine, and the potential synergetic mechanism.MethodsThe cell growth inhibition effect was monitored by the IncuCyte ZOOM Live-Cell Analysis System, and cell viability was determined by Cell Counting Kit-8 assays. Apoptosis was detected by Annexin V/Propidium Iodide double staining. Death receptor 4 (DR4) was knocked down by ribonucleic acid (RNA) interference, and the effect of DR4 deletion on TRAIL sensitivity was analyzed. Methylation-specific polymerase chain reaction (PCR) was applied to determine the methylation status of DR4. The messenger RNA (mRNA) and protein expression levels were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. The expression of the DRs on the cell membrane surfaces was analyzed by flow cytometry.ResultsThe combined use of decitabine and TRAIL synergistically inhibited cell growth in 2 TRAIL-resistant cell lines. Further, decitabine augmented TRAIL-induced apoptosis in a caspase-dependent manner. The co-application of decitabine and TRAIL facilitated the activation of caspase-7, -8, -9, and poly ADP-ribose polymerase (PARP). Notably, decitabine increased the expression of DR4 at the transcriptional and post-transcriptional levels. DR4 expression on the cell membrane surfaces was also upregulated after decitabine exposure. The depletion of DR4 by specific inhibitors attenuated TRAIL-induced apoptosis and weakened the synergistic effects of decitabine and TRAIL. In addition, DR4 gene presented methylation status in SNU-1 cells. The low mRNA and protein expression of DR4 were also detected in SNU-1 cells.ConclusionsDecitabine enhances the effect of TRAIL by inhibiting the growth and inducing the apoptosis of GC cells. This is achieved by the epigenetic modification of decitabine, which upregulates DR4. Decitabine may act as a sensitizing agent of TRAIL. The combined use of decitabine and TRAIL may provide a novel idea for GC treatment.

Dataset Information

Epigenetic Anti-Cancer Treatment With a Stabilized Carbocyclic Decitabine Analogue.

Publications

Epigenetic Anti-Cancer Treatment With a Stabilized Carbocyclic Decitabine Analogue.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets