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

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

doi:10.18632/oncotarget.25733

Abstract

IntroductionThe 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.ResultsAll 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.DiscussionDisulfiram 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 MethodsOne-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.

Highlights

The overall survival rate of patients with osteosarcoma (OS) and pulmonary metastases has remained stagnant at 15–30% for several decades
Disulfiram treatment resulted in a reduced burden of OS metastatic disease compared with controls
Our group has demonstrated that OS cells with an aggressive metastatic phenotype express higher levels of Aldehyde dehydrogenase (ALDH) compared to less metastatic cells [10]

Summary

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. Pulmonary metastatic disease is present in 15–20% of patients at the time of diagnosis. The presence of metastases at diagnosis has been associated with an abysmal (10–15%) five-year survival rate. Aldehyde dehydrogenase (ALDH) is a cancer stem cell (CSC) marker. High ALDH expression has been associated with chemoresistance and CSC survival [7,8,9]. Disulfiram (DSF) is a known ALDH inhibitor that has been previously investigated in the treatment of human cancers, acting alone and as a sensitizer to more traditional cytotoxic chemotherapies [11]

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