Research Papers:

Disulfiram reduces metastatic osteosarcoma tumor burden in an immunocompetent Balb/c or-thotopic mouse model

Jared Anthony Crasto, Mitchell Stephen Fourman, Alejandro Morales-Restrepo, Adel Mahjoub, Jonathan Brendan Mandell, Kavita Ramnath, Jessica C. Tebbets, Rebecca J. Watters and Kurt Richard Weiss _

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Oncotarget. 2018; 9:30163-30172. https://doi.org/10.18632/oncotarget.25733

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Jared Anthony Crasto1,*, Mitchell Stephen Fourman1,*, Alejandro Morales-Restrepo1, Adel Mahjoub1,2, Jonathan Brendan Mandell1, Kavita Ramnath1,3, Jessica C. Tebbets1, Rebecca J. Watters1,4 and Kurt Richard Weiss1,5

1Musculoskeletal Oncology Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA

2School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

3Carnegie Mellon University, Pittsburgh, PA, USA

4Department of Pharmacology and Chemical Biology, University of Pittsburgh, PA, USA

5Departments 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


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 × 105 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.

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