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

The cover for issue 53 of Oncotarget features Figure 4, "Image depicting primary (left) and metastatic lung (right) osteosarcoma as visualized by indocyanine green dye angiography," by Crasto, et al.

Disulfiram is an FDA-approved aldehyde dehydrogenase inhibitor that reduces the metastatic phenotype of OS cells in vitro. All treatment groups displayed a significantly reduced quantitative OS metastatic burden compared with controls. Disulfiram treatment resulted in a reduced burden of OS metastatic disease compared with controls.

Kurt Richard Weiss from the Musculoskeletal Oncology Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA and the Departments of Anatomic Pathology and General Surgical Oncology, University of Pittsburgh, PA, USA said "Therapy began three weeks after injection: saline, low-dose disulfiram, high-dose disulfiram, doxorubicin, Lo DSF + DXR, and Hi DSF + DXR."

The research group has demonstrated that OS cells with an aggressive metastatic phenotype express higher levels of ALDH compared to less metastatic cells. Prior in vitro studies by the group and others have found that DSF decreases the invasiveness and alters the morphology of OS cells in culture. The purpose of the present study was to compare the efficacies of disulfiram and doxorubicin independently and in combination using a validated, immunocompetent, orthotopic murine model of metastatic OS.

The Kurt Richard Weiss research team concluded, "Future studies will focus on the optimization of DSF dosing, the utility of copper to potentially augment the efficacy of DSF, and dosing schedules that could potentially maximize the anti-metastatic effects of DSF and decrease the requirement of high doses of DXR."

Figure 4: Image depicting primary (left) and metastatic lung (right) osteosarcoma as visualized by indocyanine green dye angiography. Quantitative measurements were performed with the SPY-Elite (Novadaq).

In this study, the research team demonstrated that selinexor significantly reduces the expression of DNA damage repair proteins, prevents recovery from DNA damage, and synergizes with DNA damage–inducing chemotherapies to stimulate cell death and reduce tumor size. In addition, the extent of repair protein repression by selinexor correlates with overall sensitivity of cancer cells to the drug.

Full text - https://doi.org/10.18632/oncotarget.25733

Correspondence to - Kurt Richard Weiss - WeisKR@UPMC.edu

Keywords - osteosarcoma, disulfiram, bad, Akt, aldehyde dehydrogenase