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  1. Article: In vitro

    Tapparo, Marta / Saccu, Gabriele / Pasquino, Chiara / Fonsato, Valentina / Medana, Claudio / Schiavo, Valentina / Mecarelli, Enrica / Maccagno, Monica / Silengo, Lorenzo / Bruno, Stefania / Camussi, Giovanni / Herrera Sanchez, Maria Beatriz

    Frontiers in cell and developmental biology

    2024  Volume 12, Page(s) 1352013

    Abstract: Introduction: ...

    Abstract Introduction:
    Language English
    Publishing date 2024-02-08
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2737824-X
    ISSN 2296-634X
    ISSN 2296-634X
    DOI 10.3389/fcell.2024.1352013
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Euchromatic Histone Lysine Methyltransferase 2 Inhibition Enhances Carfilzomib Sensitivity and Overcomes Drug Resistance in Multiple Myeloma Cell Lines.

    Mereu, Elisabetta / Abbo, Damiano / Paradzik, Tina / Cumerlato, Michela / Bandini, Cecilia / Labrador, Maria / Maccagno, Monica / Ronchetti, Domenica / Manicardi, Veronica / Neri, Antonino / Piva, Roberto

    Cancers

    2023  Volume 15, Issue 8

    Abstract: Proteasome inhibitors (PIs) are extensively used for the therapy of multiple myeloma. However, patients continuously relapse or are intrinsically resistant to this class of drugs. In addition, adverse toxic effects such as peripheral neuropathy and ... ...

    Abstract Proteasome inhibitors (PIs) are extensively used for the therapy of multiple myeloma. However, patients continuously relapse or are intrinsically resistant to this class of drugs. In addition, adverse toxic effects such as peripheral neuropathy and cardiotoxicity could arise. Here, to identify compounds that can increase the efficacy of PIs, we performed a functional screening using a library of small-molecule inhibitors covering key signaling pathways. Among the best synthetic lethal interactions, the euchromatic histone-lysine N-methyltransferase 2 (EHMT2) inhibitor UNC0642 displayed a cooperative effect with carfilzomib (CFZ) in numerous multiple myeloma (MM) cell lines, including drug-resistant models. In MM patients, EHMT2 expression correlated to worse overall and progression-free survival. Moreover, EHMT2 levels were significantly increased in bortezomib-resistant patients. We demonstrated that CFZ/UNC0642 combination exhibited a favorable cytotoxicity profile toward peripheral blood mononuclear cells and bone-marrow-derived stromal cells. To exclude off-target effects, we proved that UNC0642 treatment reduces EHMT2-related molecular markers and that an alternative EHMT2 inhibitor recapitulated the synergistic activity with CFZ. Finally, we showed that the combinatorial treatment significantly perturbs autophagy and the DNA damage repair pathways, suggesting a multi-layered mechanism of action. Overall, the present study demonstrates that EHMT2 inhibition could provide a valuable strategy to enhance PI sensitivity and overcome drug resistance in MM patients.
    Language English
    Publishing date 2023-04-07
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers15082199
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Lysin (K)-specific demethylase 1 inhibition enhances proteasome inhibitor response and overcomes drug resistance in multiple myeloma.

    Bandini, Cecilia / Mereu, Elisabetta / Paradzik, Tina / Labrador, Maria / Maccagno, Monica / Cumerlato, Michela / Oreglia, Federico / Prever, Lorenzo / Manicardi, Veronica / Taiana, Elisa / Ronchetti, Domenica / D'Agostino, Mattia / Gay, Francesca / Larocca, Alessandra / Besse, Lenka / Merlo, Giorgio Roberto / Hirsch, Emilio / Ciarrocchi, Alessia / Inghirami, Giorgio /
    Neri, Antonino / Piva, Roberto

    Experimental hematology & oncology

    2023  Volume 12, Issue 1, Page(s) 71

    Abstract: Background: Multiple myeloma (MM) is an incurable plasma cell malignancy, accounting for approximately 1% of all cancers. Despite recent advances in the treatment of MM, due to the introduction of proteasome inhibitors (PIs) such as bortezomib (BTZ) and ...

    Abstract Background: Multiple myeloma (MM) is an incurable plasma cell malignancy, accounting for approximately 1% of all cancers. Despite recent advances in the treatment of MM, due to the introduction of proteasome inhibitors (PIs) such as bortezomib (BTZ) and carfilzomib (CFZ), relapses and disease progression remain common. Therefore, a major challenge is the development of novel therapeutic approaches to overcome drug resistance, improve patient outcomes, and broaden PIs applicability to other pathologies.
    Methods: We performed genetic and drug screens to identify new synthetic lethal partners to PIs, and validated candidates in PI-sensitive and -resistant MM cells. We also tested best synthetic lethal interactions in other B-cell malignancies, such as mantle cell, Burkitt's and diffuse large B-cell lymphomas. We evaluated the toxicity of combination treatments in normal peripheral blood mononuclear cells (PBMCs) and bone marrow stromal cells (BMSCs). We confirmed the combo treatment' synergistic effects ex vivo in primary CD138+ cells from MM patients, and in different MM xenograft models. We exploited RNA-sequencing and Reverse-Phase Protein Arrays (RPPA) to investigate the molecular mechanisms of the synergy.
    Results: We identified lysine (K)-specific demethylase 1 (LSD1) as a top candidate whose inhibition can synergize with CFZ treatment. LSD1 silencing enhanced CFZ sensitivity in both PI-resistant and -sensitive MM cells, resulting in increased tumor cell death. Several LSD1 inhibitors (SP2509, SP2577, and CC-90011) triggered synergistic cytotoxicity in combination with different PIs in MM and other B-cell neoplasms. CFZ/SP2509 treatment exhibited a favorable cytotoxicity profile toward PBMCs and BMSCs. We confirmed the clinical potential of LSD1-proteasome inhibition in primary CD138+ cells of MM patients, and in MM xenograft models, leading to the inhibition of tumor progression. DNA damage response (DDR) and proliferation machinery were the most affected pathways by CFZ/SP2509 combo treatment, responsible for the anti-tumoral effects.
    Conclusions: The present study preclinically demonstrated that LSD1 inhibition could provide a valuable strategy to enhance PI sensitivity and overcome drug resistance in MM patients and that this combination might be exploited for the treatment of other B-cell malignancies, thus extending the therapeutic impact of the project.
    Language English
    Publishing date 2023-08-10
    Publishing country England
    Document type Journal Article
    ZDB-ID 2669066-4
    ISSN 2162-3619
    ISSN 2162-3619
    DOI 10.1186/s40164-023-00434-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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