Abstract
Of the deaths attributed to cancer, 90% are due to metastasis. Treatments that prevent or cure metastasis remain elusive. Low expression of extracellular superoxide dismutase (EcSOD or SOD3) has been associated with poor outcomes and increased metastatic potential in multiple types of cancer. Here, we characterize the antimetastatic therapeutic mechanisms of a macromolecular extracellular SOD3-mimetic polynitroxyl albumin (PNA, also known as VACNO). PNA is macromolecular human serum albumin conjugated with multiple nitroxide groups and acts as an SOD-mimetic. Here we show that PNA works as a SOD3-mimetic in a highly metastatic 4T1 mouse model of triple negative breast cancer (TNBC). In vitro, PNA dose dependently inhibited 4T1 proliferation, colony formation, and reactive oxygen species (ROS) formation. In vivo, PNA enhanced reperfusion time in the hypoxic cores of 4T1 tumors as measured by ultrasound imaging. Furthermore, PNA enhanced ultrasound signal intensity within the cores of the 4T1 tumors, indicating PNA can increase blood flow and blood volume within the hypoxic cores of tumors. Lung metastasis from 4T1 flank tumor was inhibited by PNA in the presence or absence of doxorubicin, a chemotherapy agent that produces superoxide and promotes metastasis. In a separate study, PNA increased the survival of mice with 4T1 flank tumors when used in conjunction with three standard chemotherapy drugs (paclitaxel, doxorubicin, and cyclophosphamide), as compared to treatment with chemotherapy alone. In this study, PNA-increased survival was also correlated with reduction of lung metastasis. These results support the hypothesis that PNA works through the inhibition of extracellular superoxide/ROS production leading to the conversion of 4T1 cells from a metastatic tumorigenic state to a cytostatic state. These findings support future clinical trials of PNA as an antimetastatic SOD3-mimetic drug to increase overall survival in TNBC patients.
Highlights
The development of antimetastatic drugs is urgently needed to reduce cancer-related deaths caused by metastasis [1]
4T1 cells treated with PNA had significantly reduced reactive oxygen species (ROS) as compared to the corresponding control human serum albumin (HSA) treatment (Figure 2)
We found that PNA reduced lung metastasis as compared to control HSA treatment but not to a level of significance (Figure 7(b), p=0.056)
Summary
The development of antimetastatic drugs is urgently needed to reduce cancer-related deaths caused by metastasis [1]. As there are no currently available targeted therapies for this aggressive disease, we hypothesized that a new treatment which targets the overproduction of extracellular superoxide and its related reactive oxygen species (ROS) may have a major impact on survival of these patients [4, 5]. We examine the efficacy of PNA, an extracellular superoxide dismutase (EcSOD or SOD3) mimetic that was originally developed for ischemic stroke [6, 7]. PNA is expected to increase the Golden Hour for treatment via its remarkable ability to treat both ischemic and hemorrhagic stroke safely without neuroimaging before thrombolytic therapy.
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