Autophagy: a novel mechanism of synergistic cytotoxicity between doxorubicin and roscovitine in a sarcoma model
| Autor: | Laurent Meijer, Gordon B. Mills, Khandan Keyomarsi, Donald H. Lambert, Laura A. Lambert, Na Qiao, Kelly K. Hunt |
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| Přispěvatelé: | Biogéosciences [UMR 6282] (BGS), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Program in integrative biology. Research Institute, The Hospital for sick children [Toronto] (SickKids), Unité de Chimie Pharmaceutique et Radiopharmacie (UCL-CMFA 7340), Université Catholique de Louvain = Catholic University of Louvain (UCL), School of Environmental Sciences [Norwich], University of East Anglia [Norwich] (UEA), Molécules et cibles thérapeutiques (MCT), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Biogéosciences [UMR 6282] [Dijon] (BGS), Centre National de la Recherche Scientifique (CNRS)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Biogéosciences [Dijon] ( BGS ), AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne ( UB ) -Centre National de la Recherche Scientifique ( CNRS ), The Hospital for Sick Children, Unité de Chimie Pharmaceutique et Radiopharmacie ( UCL-CMFA 7340 ), Université Catholique de Louvain ( UCL ), University of East Anglia [Norwich] ( UEA ), Molécules et cibles thérapeutiques ( MCT ), Centre National de la Recherche Scientifique ( CNRS ) |
| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Cancer Research
Cell cycle checkpoint MESH : Antineoplastic Combined Chemotherapy Protocols medicine.medical_treatment Apoptosis MESH : Models Biological Pharmacology MESH: Drug Synergism 0302 clinical medicine MESH : Tumor Cells Cultured MESH : Cytotoxins Antineoplastic Combined Chemotherapy Protocols Tumor Cells Cultured MESH : G2 Phase MESH : Purines Cytotoxicity Tumor Stem Cell Assay 0303 health sciences Cytotoxins MESH: Tumor Stem Cell Assay Drug Synergism Sarcoma MESH: Purines Cell cycle 3. Good health MESH: Antineoplastic Combined Chemotherapy Protocols Oncology 030220 oncology & carcinogenesis MESH: Cytotoxins medicine.drug G2 Phase MESH : Drug Synergism MESH : Tumor Stem Cell Assay [SDV.BC]Life Sciences [q-bio]/Cellular Biology Biology MESH : Sarcoma Models Biological Article 03 medical and health sciences MESH: Doxorubicin Therapeutic index medicine Autophagy Roscovitine MESH : Doxorubicin MESH: Autophagy Humans Doxorubicin MESH: Tumor Cells Cultured 030304 developmental biology Chemotherapy MESH: Humans [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology MESH: Apoptosis MESH : Humans MESH: Models Biological MESH : Autophagy MESH: G2 Phase Purines MESH: Sarcoma MESH : Apoptosis |
| Zdroj: | Cancer Research Cancer Research, 2008, 68 (19), pp.7966-74. ⟨10.1158/0008-5472.CAN-08-1333⟩ Cancer Research, American Association for Cancer Research, 2008, 68 (19), pp.7966-74. ⟨10.1158/0008-5472.CAN-08-1333⟩ Cancer Research, American Association for Cancer Research, 2008, 68 (19), pp.7966-74. 〈10.1158/0008-5472.CAN-08-1333〉 |
| ISSN: | 0008-5472 1538-7445 |
| DOI: | 10.1158/0008-5472.CAN-08-1333⟩ |
| Popis: | Doxorubicin is a genotoxic chemotherapy agent used in treatment of a wide variety of cancers. Significant clinical side effects, including cardiac toxicity and myelosuppression, severely limit the therapeutic index of this commonly used agent and methods which improve doxorubicin efficacy could benefit many patients. Because doxorubicin cytotoxicity is cell cycle specific, the cell cycle is a rational target to enhance its efficacy. We examined the direct, cyclin-dependent kinase inhibitor roscovitine as a means of enhancing doxorubicin cytotoxicity. This study showed synergistic cytotoxicity between doxorubicin and roscovitine in three sarcoma cell lines: SW-982 (synovial sarcoma), U2OS-LC3-GFP (osteosarcoma), and SK-LMS-1 (uterine leiomyosarcoma), but not the fibroblast cell line WI38. The combined treatment of doxorubicin and roscovitine was associated with a prolonged G2-M cell cycle arrest in the three sarcoma cell lines. Using three different methods for detecting apoptosis, our results revealed that apoptotic cell death did not account for the synergistic cytotoxicity between doxorubicin and roscovitine. However, morphologic changes observed by light microscopy and increased cytoplasmic LC3-GFP puncta in U20S-LC3-GFP cells after the combined treatment suggested the induction of autophagy. Induction of autophagy was also shown in SW-982 and SK-LMS-1 cells treated with both doxorubicin and roscovitine by acridine orange staining. These results suggest a novel role of autophagy in the enhanced cytotoxicity by cell cycle inhibition after genotoxic injury in tumor cells. Further investigation of this enhanced cytotoxicity as a treatment strategy for sarcomas is warranted. [Cancer Res 2008;68(19):7966–74] |
| Databáze: | OpenAIRE |
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