Global DNA hypermethylation-associated cancer chemotherapy resistance and its reversion with the demethylating agent hydralazine

Segura-Pacheco, Blanca; Pérez-Cárdenas, Enrique; Taja‐Chayeb, Lucía; Chávez‐Blanco, Alma; Revilla-Vázquez, Alma; Benı́tez-Bribiesca, Luis; Dueñas‐González, Alfonso

doi:10.1186/1479-5876-4-32

Cited by 75 publications

(32 citation statements)

References 40 publications

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“…Chemotherapy is an important factor to consider when investigating DNA methylation changes, as some studies suggest that chemotherapy can result in increased DNA methylation. [30][31][32] Apart from the Alu repetitive element, our results show no significant difference in the methylation levels of cases who underwent treatment with 5FU and those who did not, suggesting that 5FU in the MUTYH gene as previously described. 49 Those cases carrying a pathogenic mutation in a mismatch repair gene (Lynch Syndrome) or biallelic or compound heterozygous mutations in MUTYH were identified for the stratified analysis.…”

Section: Methodssupporting

confidence: 70%

Association between hypermethylation of DNA repetitive elements in white blood cell DNA and early-onset colorectal cancer

et al. 2013

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Changes in the methylation levels of DNA from white blood cells (WBCs) are putatively associated with an elevated risk for several cancers. The aim of this study was to investigate the association between colorectal cancer (CRC) and the methylation status of three DNA repetitive elements in DNA from peripheral blood. WBC DNA from 539 CRC cases diagnosed before 60 years of age and 242 sex and age frequency-matched healthy controls from the Australasian Colorectal Cancer Family Registry were assessed for methylation across DNA repetitive elements Alu, LINE-1 and Sat2 using MethyLight. The percentage of methylated reference (PMR) of cases and controls was calculated for each marker. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression adjusted for potential confounders. CRC cases demonstrated a significantly higher median PMR for LINE-1 (p < 0.001), Sat2 (p < 0.001) and Alu repeats (p = 0.02) when compared with controls. For each of the DNA repetitive elements, individuals with PMR values in the highest quartile were significantly more likely to have CRC compared with those in the lowest quartile (LINE-1 OR = 2.34, 95%CI = 1.48-3.70; p < 0.001, Alu OR = 1.83, 95%CI = 1.17-2.86; p = 0.01, Sat2 OR = 1.72, 95%CI = 1.10-2.71; p = 0.02). When comparing the OR for the PMR of each marker across subgroups of CRC, only the Alu marker showed a significant difference in the 5-fluoruracil treated and nodal involvement subgroups (both p = 0.002). This association between increasing methylation levels of three DNA repetitive elements in WBC DNA and early-onset CRC is novel and may represent a potential epigenetic biomarker for early CRC detection.

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Section: Methodssupporting

confidence: 70%

Association between hypermethylation of DNA repetitive elements in white blood cell DNA and early-onset colorectal cancer

et al. 2013

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“…To analyze promoter methylation cytotoxic chemotherapeutic drug resistance as well as the initiation and progression of cancer due to the repressed transcription. [8][9][10][11][12][13] Treatment-related DNA hypermethylation may play a role in creating drug-resistant phenotypes by inactivating genes that are required for cytotoxicity. For example, promoter methylation of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) contributes to resistance to carmustine (BCNU), 9 while methylation of FANCF is associated with acquired cisplatin resistance in ovarian cancer.…”

Section: Identification Of Dapk As a Commonly Methylated Candidate Gementioning

confidence: 99%

Methylation of death-associated protein kinase is associated with cetuximab and erlotinib resistance

et al. 2012

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Anti-EGFR therapy is among the most promising molecular targeted therapies against cancer developed in the past decade. However, drug resistance eventually arises in most, if not all, treated patients. Emerging evidence has linked epigenetic changes, such as DNA methylation at CpG islands, to the development of resistance to multiple anticancer drugs. In addition, genes that are differentially methylated have increasingly been appreciated as a source of clinically relevant biomarker candidates. To identify genes that are specifically methylated during the evolution of resistance to anti-EGFR therapeutic agents, we performed a methylation-specific array containing a panel of 56 genes that are commonly known to be regulated through promoter methylation in two parental non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC) cell lines and their resistant derivatives to either erlotinib or cetuximab. We found that death-associated protein kinase (DAPK) was hypermethylated in drug-resistant derivatives generated from both parental cell lines. Restoration of DAPK into the resistant NSCLC cells by stable transfection re-sensitized the cells to both erlotinib and cetuximab. Conversely, siRNA-mediated knockdown of DAPK induced resistance in the parental sensitive cells. These results demonstrate that DAPK plays important roles in both cetuximab and erlotinib resistance, and that gene silencing through promoter methylation is one of the key mechanisms of developed resistance to anti-EGFR therapeutic agents. In conclusion, DAPK could be a novel target to overcome resistance to anti-EGFR agents to improve the therapeutic benefit, and further evaluation of DAPK methylation as a potential biomarker of drug response is needed.

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“…25, 26 By reversing the hypermethylation state of DNA, DAC can reduce DNA methyl transferase (DNMT) activity and the expression of multidrug resistance-1 (mdr1) efflux protein, thus enhancing intracellular doxorubicin levels. 22, 23 Doxorubicin sensitivity could also depend on the state of the cell's chromatin. Highly condensed chromatin, a form observed in many cancers, restricts the toxicity of doxorubicin by limiting the accessibility of both the drug and its substrate (Topo II) to DNA.…”

Section: Introductionmentioning

confidence: 99%

Highly Synergistic Effect of Sequential Treatment with Epigenetic and Anticancer Drugs To Overcome Drug Resistance in Breast Cancer Cells Is Mediated via Activation ofp21Gene Expression Leading to G2/M Cycle Arrest

et al. 2012

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Epigenetic alterations such as aberrant DNA methylation and histone modifications contribute substantially to both the cause and maintenance of drug resistance. These epigenetic changes lead to silencing of tumor suppressor genes involved in key DNA damage-response pathways, making drug-resistant cancer cells nonresponsive to conventional anticancer drug therapies. Our hypothesis is that treating drug-resistant cells with epigenetic drugs could restore the sensitivity to anticancer drugs by reactivating previously silenced genes. To test our hypothesis, we used drug-resistant breast cancer cells (MCF-7/ADR) and two epigenetic drugs that act via different mechanisms—5-aza-2′ deoxycytidine (Decitabine, DAC), a demethylating agent and suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor—in combination with doxorubicin. We show that the sequential treatment of resistant cells, first with an epigenetic drug (DAC), and then with doxorubicin, induces a highly synergistic effect, thus reducing the IC50 of doxorubicin by several thousand folds. The sequential treatment caused over 90% resistant cells to undergo G2/M cell cycle arrest, determined to be due to upregulation of p21WAF1/CIP1 expression, which is responsible for cell-cycle regulation. The induction of p21WAF1/CIP1 correlated well with the depletion of DNA methyltransferase1 (DNMT1), an enzyme that promotes methylation of DNA, suggesting that the p21WAF1/CIP1 gene may have been methylated and hence is inactive in MCF-7/ADR cells. Microarray analysis shows expression of several tumor suppressor genes and downregulation of tumor promoter genes, particularly in sequentially treated resistant cells. Sequential treatment was found to be significantly more effective than simultaneous treatment, and DAC was more effective than SAHA in overcoming doxorubicin resistance. Synergistic effect with sequential treatment was also seen in drug-sensitive breast cancer cells, but the effect was significantly more pronounced in resistant cells. In conclusion, the sequential treatment of an epigenetic drug in combination with doxorubicin induces a highly synergistic effect that overcomes doxorubicin resistance in breast cancer cells.

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Global DNA hypermethylation-associated cancer chemotherapy resistance and its reversion with the demethylating agent hydralazine

Cited by 75 publications

References 40 publications

Association between hypermethylation of DNA repetitive elements in white blood cell DNA and early-onset colorectal cancer

Association between hypermethylation of DNA repetitive elements in white blood cell DNA and early-onset colorectal cancer

Methylation of death-associated protein kinase is associated with cetuximab and erlotinib resistance

Highly Synergistic Effect of Sequential Treatment with Epigenetic and Anticancer Drugs To Overcome Drug Resistance in Breast Cancer Cells Is Mediated via Activation ofp21Gene Expression Leading to G2/M Cycle Arrest

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