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  1. Article ; Online: Methylglyoxal: a novel upstream regulator of DNA methylation.

    Dube, Gaurav / Tiamiou, Assia / Bizet, Martin / Boumahd, Yasmine / Gasmi, Imène / Crake, Rebekah / Bellier, Justine / Nokin, Marie-Julie / Calonne, Emilie / Deplus, Rachel / Wissocq, Tom / Peulen, Olivier / Castronovo, Vincent / Fuks, François / Bellahcène, Akeila

    Journal of experimental & clinical cancer research : CR

    2023  Volume 42, Issue 1, Page(s) 78

    Abstract: Background: Aerobic glycolysis, also known as the Warburg effect, is predominantly upregulated in a variety of solid tumors, including breast cancer. We have previously reported that methylglyoxal (MG), a very reactive by-product of glycolysis, ... ...

    Abstract Background: Aerobic glycolysis, also known as the Warburg effect, is predominantly upregulated in a variety of solid tumors, including breast cancer. We have previously reported that methylglyoxal (MG), a very reactive by-product of glycolysis, unexpectedly enhanced the metastatic potential in triple negative breast cancer (TNBC) cells. MG and MG-derived glycation products have been associated with various diseases, such as diabetes, neurodegenerative disorders, and cancer. Glyoxalase 1 (GLO1) exerts an anti-glycation defense by detoxifying MG to D-lactate.
    Methods: Here, we used our validated model consisting of stable GLO1 depletion to induce MG stress in TNBC cells. Using genome-scale DNA methylation analysis, we report that this condition resulted in DNA hypermethylation in TNBC cells and xenografts.
    Results: GLO1-depleted breast cancer cells showed elevated expression of DNMT3B methyltransferase and significant loss of metastasis-related tumor suppressor genes, as assessed using integrated analysis of methylome and transcriptome data. Interestingly, MG scavengers revealed to be as potent as typical DNA demethylating agents at triggering the re-expression of representative silenced genes. Importantly, we delineated an epigenomic MG signature that effectively stratified TNBC patients based on survival.
    Conclusion: This study emphasizes the importance of MG oncometabolite, occurring downstream of the Warburg effect, as a novel epigenetic regulator and proposes MG scavengers to reverse altered patterns of gene expression in TNBC.
    MeSH term(s) Humans ; DNA Methylation ; Triple Negative Breast Neoplasms/metabolism ; Pyruvaldehyde/metabolism ; Cell Line, Tumor ; Transcriptome ; Gene Expression Regulation, Neoplastic
    Chemical Substances Pyruvaldehyde (722KLD7415)
    Language English
    Publishing date 2023-03-31
    Publishing country England
    Document type Journal Article
    ZDB-ID 803138-1
    ISSN 1756-9966 ; 0392-9078
    ISSN (online) 1756-9966
    ISSN 0392-9078
    DOI 10.1186/s13046-023-02637-w
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2065: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  2. Article ; Online: Influence of serum inflammatory cytokines on cytochrome P450 drug metabolising activity during breast cancer chemotherapy: a patient feasibility study.

    Crake, Rebekah L I / Strother, Matthew R / Phillips, Elisabeth / Doogue, Matthew P / Zhang, Mei / Frampton, Chris M A / Robinson, Bridget A / Currie, Margaret J

    Scientific reports

    2021  Volume 11, Issue 1, Page(s) 5648

    Abstract: Individual response to chemotherapy in patients with breast cancer is variable. Obesity and exercise are associated with better and worse outcomes, respectively, and it is known that both impact the systemic cytokine milieu. Cytochrome P450 (CYP) enzymes ...

    Abstract Individual response to chemotherapy in patients with breast cancer is variable. Obesity and exercise are associated with better and worse outcomes, respectively, and it is known that both impact the systemic cytokine milieu. Cytochrome P450 (CYP) enzymes are responsible for the metabolism of many chemotherapy agents, and CYP enzyme activity has been shown to be modified by inflammatory cytokines in vitro and in vivo. Cytokine-associated changes in CYP metabolism may alter chemotherapy exposure, potentially affecting treatment response and patient survival. Therefore, better understanding of these biological relationships is required. This exploratory single arm open label trial investigated changes in in vivo CYP activity in twelve women treated for stage II or III breast cancer, and demonstrated for the first time the feasibility and safety of utilising the Inje phenotyping cocktail to measure CYP activity in cancer patients receiving chemotherapy. Relative CYP activity varied between participants, particularly for CYP2C9 and CYP2D6, and changes in serum concentrations of the inflammatory cytokine monocyte chemoattractant protein 1 inversely correlated to CYP3A4 activity during chemotherapy. Future use of phenotyping cocktails in a clinical oncology setting may help guide drug dosing and improve chemotherapy outcomes.Clinical Trial Registration: Trial was retrospectively registered to the Australia New Zealand Clinical Trial Registry (ANZCTR). ACTRN12620000832976, 21 Aug 2020, https://www.anzctr.org.au/ACTRN12620000832976.aspx .
    MeSH term(s) Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Breast Neoplasms/blood ; Breast Neoplasms/drug therapy ; Cytochrome P-450 Enzyme System/metabolism ; Cytokines/blood ; Feasibility Studies ; Female ; Humans ; Inflammation Mediators/blood
    Chemical Substances Antineoplastic Agents ; Cytokines ; Inflammation Mediators ; Cytochrome P-450 Enzyme System (9035-51-2)
    Language English
    Publishing date 2021-03-11
    Publishing country England
    Document type Clinical Trial ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-021-85048-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: The Role of 2-Oxoglutarate Dependent Dioxygenases in Gliomas and Glioblastomas: A Review of Epigenetic Reprogramming and Hypoxic Response.

    Crake, Rebekah L I / Burgess, Eleanor R / Royds, Janice A / Phillips, Elisabeth / Vissers, Margreet C M / Dachs, Gabi U

    Frontiers in oncology

    2021  Volume 11, Page(s) 619300

    Abstract: Gliomas are a heterogeneous group of cancers that predominantly arise from glial cells in the brain, but may also arise from neural stem cells, encompassing low-grade glioma and high-grade glioblastoma. Whereas better diagnosis and new treatments have ... ...

    Abstract Gliomas are a heterogeneous group of cancers that predominantly arise from glial cells in the brain, but may also arise from neural stem cells, encompassing low-grade glioma and high-grade glioblastoma. Whereas better diagnosis and new treatments have improved patient survival for many cancers, glioblastomas remain challenging with a highly unfavorable prognosis. This review discusses a super-family of enzymes, the 2-oxoglutarate dependent dioxygenase enzymes (2-OGDD) that control numerous processes including epigenetic modifications and oxygen sensing, and considers their many roles in the pathology of gliomas. We specifically describe in more detail the DNA and histone demethylases, and the hypoxia-inducible factor hydroxylases in the context of glioma, and discuss the substrate and cofactor requirements of the 2-OGDD enzymes. Better understanding of how these enzymes contribute to gliomas could lead to the development of new treatment strategies.
    Language English
    Publishing date 2021-03-25
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2649216-7
    ISSN 2234-943X
    ISSN 2234-943X
    DOI 10.3389/fonc.2021.619300
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Co-culture With Human Breast Adipocytes Differentially Regulates Protein Abundance in Breast Cancer Cells.

    Lee Isla Crake, Rebekah / Phillips, Elisabeth / Kleffmann, Torsten / Currie, Margaret Jane

    Cancer genomics & proteomics

    2019  Volume 16, Issue 5, Page(s) 319–332

    Abstract: Background/aim: Recent research highlights the role of cancer-associated adipocytes (CAA) in promoting breast cancer cell migration, invasion and resistance to therapy. This study aimed at identifying cellular proteins differentially regulated in breast ...

    Abstract Background/aim: Recent research highlights the role of cancer-associated adipocytes (CAA) in promoting breast cancer cell migration, invasion and resistance to therapy. This study aimed at identifying cellular proteins differentially regulated in breast cancer cells co-cultured with CAA.
    Materials and methods: Adipocytes isolated from human breast adipose tissue were co-cultured with hormone receptor-positive (MCF-7) or -negative (MDA-MB-231) breast cancer cells using a transwell co-culture system. Proteomes of co-cultured and control breast cancer cells were compared quantitatively using iTRAQ labelling and tandem mass spectrometry, and the results were validated by western blotting.
    Results: A total of 1,126 and 1,218 proteins were identified in MCF-7 and MDA-MB-231 cells, respectively. Among these, 85 (MCF-7) and 63 (MDA-MB-231) had an average fold change >1.5 following co-culture. Pathway analysis revealed that CAA-induced enrichment of proteins involved in metabolism, the ubiquitin proteasome, and purine synthesis.
    Conclusion: This study provides a proteomic platform for investigating the paracrine role of CAA in promoting breast cancer cell metastasis and resistance to therapy.
    MeSH term(s) Adipocytes ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Cell Differentiation ; Cell Line, Tumor ; Coculture Techniques/methods ; Female ; Humans ; Tumor Microenvironment
    Language English
    Publishing date 2019-08-26
    Publishing country Greece
    Document type Journal Article
    ZDB-ID 2144517-5
    ISSN 1790-6245 ; 1109-6535
    ISSN (online) 1790-6245
    ISSN 1109-6535
    DOI 10.21873/cgp.20137
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5873: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  5. Article ; Online: Resistance to Gemcitabine in Pancreatic Cancer Is Connected to Methylglyoxal Stress and Heat Shock Response.

    Crake, Rebekah / Gasmi, Imène / Dehaye, Jordan / Lardinois, Fanny / Peiffer, Raphaël / Maloujahmoum, Naïma / Agirman, Ferman / Koopmansch, Benjamin / D'Haene, Nicky / Azurmendi Senar, Oier / Arsenijevic, Tatjana / Lambert, Frédéric / Peulen, Olivier / Van Laethem, Jean-Luc / Bellahcène, Akeila

    Cells

    2023  Volume 12, Issue 10

    Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with poor prognosis. Gemcitabine is the first-line therapy for PDAC, but gemcitabine resistance is a major impediment to achieving satisfactory clinical outcomes. This study investigated whether ... ...

    Abstract Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with poor prognosis. Gemcitabine is the first-line therapy for PDAC, but gemcitabine resistance is a major impediment to achieving satisfactory clinical outcomes. This study investigated whether methylglyoxal (MG), an oncometabolite spontaneously formed as a by-product of glycolysis, notably favors PDAC resistance to gemcitabine. We observed that human PDAC tumors expressing elevated levels of glycolytic enzymes together with high levels of glyoxalase 1 (GLO1), the major MG-detoxifying enzyme, present with a poor prognosis. Next, we showed that glycolysis and subsequent MG stress are triggered in PDAC cells rendered resistant to gemcitabine when compared with parental cells. In fact, acquired resistance, following short and long-term gemcitabine challenges, correlated with the upregulation of GLUT1, LDHA, GLO1, and the accumulation of MG protein adducts. We showed that MG-mediated activation of heat shock response is, at least in part, the molecular mechanism underlying survival in gemcitabine-treated PDAC cells. This novel adverse effect of gemcitabine, i.e., induction of MG stress and HSR activation, is efficiently reversed using potent MG scavengers such as metformin and aminoguanidine. We propose that the MG blockade could be exploited to resensitize resistant PDAC tumors and to improve patient outcomes using gemcitabine therapy.
    MeSH term(s) Humans ; Gemcitabine ; Pyruvaldehyde ; Deoxycytidine/pharmacology ; Deoxycytidine/therapeutic use ; Antimetabolites, Antineoplastic/pharmacology ; Pancreatic Neoplasms/pathology ; Carcinoma, Pancreatic Ductal/metabolism ; Heat-Shock Response ; Pancreatic Neoplasms
    Chemical Substances Gemcitabine ; Pyruvaldehyde (722KLD7415) ; Deoxycytidine (0W860991D6) ; Antimetabolites, Antineoplastic
    Language English
    Publishing date 2023-05-17
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells12101414
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Increased Ascorbate Content of Glioblastoma Is Associated With a Suppressed Hypoxic Response and Improved Patient Survival.

    Burgess, Eleanor R / Crake, Rebekah L I / Phillips, Elisabeth / Morrin, Helen R / Royds, Janice A / Slatter, Tania L / Wiggins, George A R / Vissers, Margreet C M / Robinson, Bridget A / Dachs, Gabi U

    Frontiers in oncology

    2022  Volume 12, Page(s) 829524

    Abstract: Glioblastoma multiforme is a challenging disease with limited treatment options and poor survival. Glioblastoma tumours are characterised by hypoxia that activates the hypoxia inducible factor (HIF) pathway and controls a myriad of genes that drive ... ...

    Abstract Glioblastoma multiforme is a challenging disease with limited treatment options and poor survival. Glioblastoma tumours are characterised by hypoxia that activates the hypoxia inducible factor (HIF) pathway and controls a myriad of genes that drive cancer progression. HIF transcription factors are regulated at the post-translation level
    Language English
    Publishing date 2022-03-28
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2649216-7
    ISSN 2234-943X
    ISSN 2234-943X
    DOI 10.3389/fonc.2022.829524
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Ascorbate content of clinical glioma tissues is related to tumour grade and to global levels of 5-hydroxymethyl cytosine.

    Crake, Rebekah L I / Burgess, Eleanor R / Wiggins, George A R / Magon, Nicholas J / Das, Andrew B / Vissers, Margreet C M / Morrin, Helen R / Royds, Janice A / Slatter, Tania L / Robinson, Bridget A / Phillips, Elisabeth / Dachs, Gabi U

    Scientific reports

    2022  Volume 12, Issue 1, Page(s) 14845

    Abstract: Gliomas are incurable brain cancers with poor prognosis, with epigenetic dysregulation being a distinctive feature. 5-hydroxymethylcytosine (5-hmC), an intermediate generated in the demethylation of 5-methylcytosine, is present at reduced levels in ... ...

    Abstract Gliomas are incurable brain cancers with poor prognosis, with epigenetic dysregulation being a distinctive feature. 5-hydroxymethylcytosine (5-hmC), an intermediate generated in the demethylation of 5-methylcytosine, is present at reduced levels in glioma tissue compared with normal brain, and that higher levels of 5-hmC are associated with improved patient survival. DNA demethylation is enzymatically driven by the ten-eleven translocation (TET) dioxygenases that require ascorbate as an essential cofactor. There is limited data on ascorbate in gliomas and the relationship between ascorbate and 5-hmC in gliomas has never been reported. Clinical glioma samples (11 low-grade, 26 high-grade) were analysed for ascorbate, global DNA methylation and hydroxymethylation, and methylation status of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter. Low-grade gliomas contained significantly higher levels of ascorbate than high-grade gliomas (p = 0.026). Levels of 5-hmC were significantly higher in low-grade than high-grade glioma (p = 0.0013). There was a strong association between higher ascorbate and higher 5-hmC (p = 0.004). Gliomas with unmethylated and methylated MGMT promoters had similar ascorbate levels (p = 0.96). One mechanism by which epigenetic modifications could occur is through ascorbate-mediated optimisation of TET activity in gliomas. These findings open the door to clinical intervention trials in patients with glioma to provide both mechanistic information and potential avenues for adjuvant ascorbate therapy.
    MeSH term(s) Brain Neoplasms/chemistry ; Brain Neoplasms/diagnosis ; Brain Neoplasms/pathology ; Cytosine/cerebrospinal fluid ; Cytosine/chemistry ; DNA Methylation ; Glioma/chemistry ; Glioma/diagnosis ; Glioma/pathology ; Humans ; Neoplasm Grading ; O(6)-Methylguanine-DNA Methyltransferase/genetics ; Promoter Regions, Genetic
    Chemical Substances Cytosine (8J337D1HZY) ; O(6)-Methylguanine-DNA Methyltransferase (EC 2.1.1.63)
    Language English
    Publishing date 2022-09-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-022-19032-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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