Clinical and biological effects of demethylating agents on solid tumours – A systematic review

Linnekamp, Janneke F.; Butter, Rogier; Spijker, René; Medema, Jan Paul; Laarhoven, Hanneke W. M. van

doi:10.1016/j.ctrv.2017.01.004

Cited by 116 publications

(85 citation statements)

References 85 publications

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“…Demethylating agents have been shown to be effective in the treatment of hematological malignancies, and their efficacy in solid tumors was also evaluated in a variety of solid cancers (26,47). Besides azacitidine and decitabine, which are the only demethylating drugs approved by the FDA for the treatment of MDS (48,49), other DNMT inhibitors, such as guadecitabine, hydralazine, and MG98, have been investigated as anticancer agents (47). In patients with ovarian cancer, increased sensitivity was observed toward carboplatin after treatment with either azacitidine (50) or decitabine (51,52).…”

Section: Discussionmentioning

confidence: 99%

DNA methyltransferase expression in triple-negative breast cancer predicts sensitivity to decitabine

Yu¹,

Qin²,

Moyer

et al. 2018

Journal of Clinical Investigation

141

111

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Triple-negative breast cancer (TNBC) is a heterogeneous disease with poor prognosis that lacks targeted therapies, especially in patients with chemotherapy-resistant disease. Since DNA methylation-induced silencing of tumor suppressors is common in cancer, reversal of promoter DNA hypermethylation by 5-aza-2'-deoxycytidine (decitabine), an FDA-approved DNA methyltransferase (DNMT) inhibitor, has proven effective in treating hematological neoplasms. However, its antitumor effect varies in solid tumors, stressing the importance of identifying biomarkers predictive of therapeutic response. Here, we focused on the identification of biomarkers to select decitabine-sensitive TNBC through increasing our understanding of the mechanism of decitabine action. We showed that protein levels of DNMTs correlated with response to decitabine in patient-derived xenograft (PDX) organoids originating from chemotherapy-sensitive and -resistant TNBCs, suggesting DNMT levels as potential biomarkers of response. Furthermore, all 3 methytransferases, DNMT1, DNMT3A, and DNMT3B, were degraded following low-concentration, long-term decitabine treatment both in vitro and in vivo. The DNMT proteins could be ubiquitinated by the E3 ligase, TNF receptor-associated factor 6 (TRAF6), leading to lysosome-dependent protein degradation. Depletion of TRAF6 blocked decitabine-induced DNMT degradation, conferring resistance to decitabine. Our study suggests a potential mechanism of regulating DNMT protein degradation and DNMT levels as response biomarkers for DNMT inhibitors in TNBCs.

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Section: Discussionmentioning

confidence: 99%

DNA methyltransferase expression in triple-negative breast cancer predicts sensitivity to decitabine

Yu¹,

Qin²,

Moyer

et al. 2018

Journal of Clinical Investigation

141

111

View full text Add to dashboard Cite

show abstract

“…Therefore, clinicians can combine demethylating agents with classical chemotherapeutics during therapy (Howell, Liu, & Khong, ). In particular, this was found to be helpful for the treatment of solid tumors (Linnekamp, Butter, Spijker, Medema, & van Laarhoven, ). The accuracy of the tools for the detection of cytosine modifications is crucial for the understanding of their profiles in normal development and in diseases.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, clinicians can combine demethylating agents with classical chemotherapeutics during therapy (Howell, Liu, & Khong, 2010). In particular, this was found to be helpful for the treatment of solid tumors (Linnekamp, Butter, Spijker, Medema, & van Laarhoven, 2017).…”

Section: Introductionmentioning

confidence: 99%

Enhanced immunological detection of epigenetic modifications of DNA in healthy and cancerous cells by fluorescence microscopy

Çelik-Uzuner

2019

Microsc Res Tech

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Epigenetic modifications of DNA, including methylation, hydroxymethylation, formylation, and carboxylation of cytosines, are proposed to function in gene regulation during reproduction and development. Changes in cytosine methylation are associated with a range of diseases, such as cancer. Immunofluorescence uses specific antibodies to quantitatively detect the global amount of cytosine modifications by fluorescence microscopy. The most critical stage of immunofluorescence is the antigen retrieval to remove the protein content around the DNA, allowing specific antibodies to bind to DNA epitopes. Acid treatments have commonly been used for antigen retrieval. Previously, trypsin was added after acid in the protocol, which increased the amount of detectable DNA methylation. In this study, the protocol was further enhanced by the addition of pepsin, which is able to target charged hydrophobic amino acids in proteins, unlike trypsin, which breaks positive hydrophilic amino acids. The global levels of cytosine modifications in CF‐1, HeLa, and AR42J cells were compared using this protocol. In all cells, the sequential treatment of trypsin and pepsin increased the specificity of the staining. With the synergistic effect of the two enzymes, it is possible to target different protein groups packaging DNA molecules and removing them effectively. The findings suggest that this revised protocol can be conveniently used for each cytosine modification in the cells examined, and should be optimized for other cells. These new antigen retrieval conditions may more accurately detect the changes in cytosine modifications during development and in diseases.

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“…5) Several clinical studies using DAC or AC in combination with other anticancer drugs were performed. 19) In colorectal cancer, DAC was used in combination with L-OHP and capecitabine (prodrug of 5-FU) and most of the response results from treated patients were to be classified as stable disease. SAHA is a first HDAC inhibitor approved by FDA.…”

Section: Discussionmentioning

confidence: 99%

Different Schedule-Dependent Effects of Epigenetic Modifiers on Cytotoxicity by Anticancer Drugs in Colorectal Cancer Cells

Hosokawa

Tanaka

Iwakawa

2017

Biological & Pharmaceutical Bulletin

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Limited information is currently available on how to apply epigenetic modifiers to current colorectal cancer (CRC) chemotherapy. The purpose of this study is to clarify the schedule-dependent effects of combined treatment with conventional anticancer drugs and epigenetic modifiers in human CRC cells. Cytotoxicity in 4 CRC cell lines (SW480, HT29, SW48, and HCT116) was measured using the WST-8 assay. As epigenetic modifiers, 3 DNA methyltransferase (DNMT) inhibitors such as decitabine (DAC), azacytidine (AC), and zebularine (Zeb), and 3 histone deacetylase (HDAC) inhibitors including trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA), and valproic acid (VPA) were used. Combination effects were analyzed by the isobologram method. SW480 cells showed the lowest sensitivity to the anticancer drugs 5-fluorouracil, SN-38 (the active form of irinotecan), and oxaliplatin. In SW480 cells, epigenetic modifiers other than VPA showed the most significant synergistic effects when used before anticancer drugs, while VPA showed synergistic effects in co-or post-treatment. In the 3 other CRC cells, synergistic effects were less frequent and weaker. The dose of anticancer drugs may be reduced by combining epigenetic modifiers in SW480 cells, which are less sensitive to anticancer drugs, unlike the more sensitive HT29, SW48, and HCT116 cell lines. These results provide useful information for understanding how to incorporate epigenetic modifiers into current CRC chemotherapy.Key words schedule-dependent treatment; epigenetic therapy; colorectal cancer; DNA methyltransferase inhibitor; histone deacetylase inhibitor Epigenetic alterations such as DNA methylation and histone modifications have been identified as a crucial driving force in the initiation and progression of cancer.1) Since epigenetic alterations are reversible, epigenetic modifiers may be beneficial in chemotherapy.2) Several epigenetic modifiers including DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors have been approved by U.S. Food and Drug Administration (FDA) for the treatment of cancer.Combined chemotherapy, including 5-fluorouracil (5-FU) and either irinotecan (CPT-11) or oxaliplatin (L-OHP), has improved the survival period of metastatic colorectal cancer (CRC). However, resistance to these anticancer drugs, which limits the effectiveness of chemotherapy, has been reported. 3,4) In order to overcome this issue, novel combination therapy using epigenetic modifiers is expected. Clinical trials on combination therapy have been performed using solid tumors including CRC.5,6) However, there is not enough integrated information on how to apply epigenetic modifiers to current CRC chemotherapy. We previously reported that a co-treatment with decitabine (DAC, 5-aza-2′-deoxycytidine), a DNMT inhibitor, and L-OHP exerted the most potent synergistic effects among the combinations tested using 5 epigenetic modifiers and 5-FU, CPT-11, or L-OHP in 4 different CRC cell lines. 7)The treatment schedule is important for effective cancer ...

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Clinical and biological effects of demethylating agents on solid tumours – A systematic review

Cited by 116 publications

References 85 publications

DNA methyltransferase expression in triple-negative breast cancer predicts sensitivity to decitabine

DNA methyltransferase expression in triple-negative breast cancer predicts sensitivity to decitabine

Enhanced immunological detection of epigenetic modifications of DNA in healthy and cancerous cells by fluorescence microscopy

Different Schedule-Dependent Effects of Epigenetic Modifiers on Cytotoxicity by Anticancer Drugs in Colorectal Cancer Cells

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