Disulfiram reduces metastatic osteosarcoma tumor burden in an immunocompetent Balb/c or-thotopic mouse model
| Autor: | Alejandro Morales-Restrepo, Kavita Ramnath, Jared A. Crasto, Kurt R. Weiss, Rebecca J. Watters, Jessica C. Tebbets, Jonathan B. Mandell, Adel Mahjoub, Mitchell S. Fourman |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Oncology medicine.medical_specialty medicine.medical_treatment Aldehyde dehydrogenase disulfiram BALB/c 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine aldehyde dehydrogenase Surgical oncology Internal medicine osteosarcoma Medicine Doxorubicin Chemotherapy biology business.industry Akt medicine.disease biology.organism_classification 030104 developmental biology chemistry 030220 oncology & carcinogenesis Disulfiram biology.protein Osteosarcoma bad business Indocyanine green medicine.drug Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Jared Anthony Crasto 1, * , Mitchell Stephen Fourman 1, * , Alejandro Morales-Restrepo 1 , Adel Mahjoub 1, 2 , Jonathan Brendan Mandell 1 , Kavita Ramnath 1, 3 , Jessica C. Tebbets 1 , Rebecca J. Watters 1, 4 and Kurt Richard Weiss 1, 5 1 Musculoskeletal Oncology Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA 2 School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA 3 Carnegie Mellon University, Pittsburgh, PA, USA 4 Department of Pharmacology and Chemical Biology, University of Pittsburgh, PA, USA 5 Departments of Anatomic Pathology and General Surgical Oncology, University of Pittsburgh, PA, USA * Co-first authors: These authors contributed equally to this work Correspondence to: Kurt Richard Weiss, email: WeisKR@UPMC.edu Keywords: osteosarcoma; disulfiram; bad; Akt; aldehyde dehydrogenase Abbreviations: OS: osteosarcoma; DSF: disulfiram; DXR: doxorubicin; ALDH: aldehyde dehydrogenase; ICG: indocyanine green Received: April 17, 2018 Accepted: June 14, 2018 Published: July 10, 2018 ABSTRACT Introduction: The overall survival rate of patients with osteosarcoma (OS) and pulmonary metastases has remained stagnant at 15–30% for several decades. Disulfiram (DSF) is an FDA-approved aldehyde dehydrogenase inhibitor that reduces the metastatic phenotype of OS cells in vitro . Here we evaluate its in vivo efficacy, as compared to doxorubicin chemotherapy, in a previously-validated orthotopic model of metastatic OS. Results: All treatment groups displayed a significantly reduced quantitative OS metastatic burden compared with controls. The metastatic burden of Lo DSF-treated animals was equivalent to the DXR group. Ninety-five percent of control animals displayed evidence of metastatic disease, which was significantly greater than all treatment groups. Discussion: Disulfiram treatment resulted in a reduced burden of OS metastatic disease compared with controls. This was statistically-equivalent to doxorubicin. No additive effect was observed between these two therapies. Materials and Methods: One-hundred twenty immunocompetent Balb/c mice received proximal tibia paraphyseal injections of 5 × 10 5 K7M2 murine OS cells. Therapy began three weeks after injection: saline (control), low-dose disulfiram (Lo DSF), high-dose disulfiram (Hi DSF), doxorubicin (DXR), Lo DSF + DXR, and Hi DSF + DXR. Transfemoral amputations were performed at 4 weeks. Quantitative metastatic tumor burden was measured using near-infrared indocyanine green (ICG) angiography. |
| Databáze: | OpenAIRE |
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