A Quinoline-Based DNA Methyltransferase Inhibitor as a Possible Adjuvant in Osteosarcoma Therapy
| Autor: | Roberta Mazzone, Piero Picci, Katia Scotlandi, Michela Pasello, Patrizia Nanni, Giordano Nicoletti, Maria Cristina Manara, Antonello Mai, Clara Guerzoni, Camilla Cristalli, Pier Luigi Lollini, Lorena Landuzzi, Sergio Valente, Giulia Stazi, Paola B. Arimondo, Clemens Zwergel |
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| Přispěvatelé: | Istituto Ortopedico Rizzoli [Bologna, Italy], Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Centre National de la Recherche Scientifique (CNRS), Department of Medicinal Chemistry and Technologies, Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], This work was funded by AIRC (IG 18451 to K. Scotlandi, IG 19162 to A. Mai), the Italian Ministry of Health (TRANSCAN_ project TORPEDO_ER-2015-23604059 to K. Scotlandi), Progetto Ateneo Sapienza (to A. Mai), PRIN 2016 (prot 20152TE5PK to A. Mai), and the NIH (R01GM114306 to A. Mai)., The authors thank Cristina Ghinelli for editing the manuscript., Manara, Maria Cristina, Valente, Sergio, Cristalli, Camilla, Nicoletti, Giordano, Landuzzi, Lorena, Zwergel, Clemen, Mazzone, Roberta, Stazi, Giulia, Arimondo, Paola B, Pasello, Michela, Guerzoni, Clara, Picci, Piero, Nanni, Patrizia, Lollini, Pier-Luigi, Mai, Antonello, Scotlandi, Katia |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male patient-derived xenograft (PDX) MESH: Osteosarcoma/genetics MESH: Antineoplastic Combined Chemotherapy Protocols/therapeutic use Cellular differentiation DNA Methyltransferase Inhibitor [CHIM.THER]Chemical Sciences/Medicinal Chemistry chemotherapy MESH: Mice Knockout 0302 clinical medicine MESH: Osteosarcoma/drug therapy Antineoplastic Combined Chemotherapy Protocols MESH: Aminoquinolines/administration & dosage MESH: Animals MESH: Quinolines/chemistry Enzyme Inhibitors MESH: DNA (Cytosine-5-)-Methyltransferase 1/metabolism Mice Knockout DNA methylation Chemistry 3. Good health Tumor Burden MESH: Benzamides/pharmacology Gene Expression Regulation Neoplastic 030220 oncology & carcinogenesis Benzamides oncology Aminoquinolines Quinolines MESH: Cisplatin/administration & dosage MESH: Bone Neoplasms/metabolism Osteosarcoma MESH: Doxorubicin/administration & dosage epigenetic MESH: Bone Neoplasms/genetics medicine.drug DNA (Cytosine-5-)-Methyltransferase 1 musculoskeletal diseases MESH: Aminoquinolines/pharmacology MESH: Cell Line Tumor DNA damage MESH: Gene Expression Regulation Neoplastic/drug effects MESH: Tumor Burden/genetics MESH: Xenograft Model Antitumor Assays Bone Neoplasms [SDV.CAN]Life Sciences [q-bio]/Cancer 03 medical and health sciences Cell Line Tumor osteosarcoma medicine Animals Humans Doxorubicin MESH: DNA (Cytosine-5-)-Methyltransferase 1/antagonists & inhibitors MESH: Enzyme Inhibitors/chemistry Cisplatin MESH: Humans Nucleoside inhibitor medicine.disease MESH: Enzyme Inhibitors/pharmacology Xenograft Model Antitumor Assays MESH: Male MESH: Enzyme Inhibitors/administration & dosage MESH: Bone Neoplasms/drug therapy 030104 developmental biology MESH: Osteosarcoma/metabolism Cancer research cancer research MESH: DNA (Cytosine-5-)-Methyltransferase 1/genetics MESH: Benzamides/administration & dosage MESH: Tumor Burden/drug effects |
| Zdroj: | Molecular Cancer Therapeutics Molecular Cancer Therapeutics, American Association for Cancer Research, 2018, 17 (9), pp.1881-1892. ⟨10.1158/1535-7163.MCT-17-0818⟩ |
| ISSN: | 1535-7163 1538-8514 |
| DOI: | 10.1158/1535-7163.MCT-17-0818⟩ |
| Popis: | The identification of new therapeutic strategies against osteosarcoma, the most common primary bone tumor, continues to be a primary goal to improve the outcomes of patients refractory to conventional chemotherapy. Osteosarcoma originates from the transformation of mesenchymal stem cells (MSC) and/or osteoblast progenitors, and the loss of differentiation is a common biological osteosarcoma feature, which has strong significance in predicting tumor aggressiveness. Thus, restoring differentiation through epigenetic reprogramming is potentially exploitable for therapeutic benefits. Here, we demonstrated that the novel nonnucleoside DNMT inhibitor (DNMTi) MC3343 affected tumor proliferation by blocking osteosarcoma cells in G1 or G2–M phases and induced osteoblastic differentiation through the specific reexpression of genes regulating this physiologic process. Although MC3343 has a similar antiproliferative effect as 5azadC, the conventional FDA-approved nucleoside inhibitor of DNA methylation, its effects on cell differentiation are distinct. Induction of the mature osteoblast phenotype coupled with a sustained cytostatic response was also confirmed in vivo when MC3343 was used against a patient-derived xenograft (PDX). In addition, MC3343 displayed synergistic effects with doxorubicin and cisplatin (CDDP), two major chemotherapeutic agents used to treat osteosarcoma. Specifically, MC3343 increased stable doxorubicin bonds to DNA, and combined treatment resulted in sustained DNA damage and increased cell death. Overall, this nonnucleoside DNMTi is an effective novel agent and is thus a potential therapeutic option for patients with osteosarcoma who respond poorly to preadjuvant chemotherapy. Mol Cancer Ther; 17(9); 1881–92. ©2018 AACR. |
| Databáze: | OpenAIRE |
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