Use of antimetastatic SOD3-mimetic albumin as a primer in triple negative breast cancer

Shanta M. Messerli, Amanda M. Schaefer, Yongxian Zhuang, Bohdan J. Soltys, Noah Keime, Jenny Jin, Li Ma, Carleton J.C. Hsia, W. Keith Miskimins

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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.

Original languageEnglish (US)
Article number3253696
JournalJournal of Oncology
Volume2019
DOIs
StatePublished - Jan 1 2019

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Triple Negative Breast Neoplasms
Albumins
Neoplasm Metastasis
Neoplasms
Drug Therapy
Superoxides
Doxorubicin
Reactive Oxygen Species
Lung
Survival
Cytostatic Agents
Paclitaxel
Blood Volume
Serum Albumin
Pharmaceutical Preparations
Cyclophosphamide
Superoxide Dismutase
Reperfusion
Ultrasonography
Therapeutics

ASJC Scopus subject areas

  • Oncology

Cite this

Messerli, S. M., Schaefer, A. M., Zhuang, Y., Soltys, B. J., Keime, N., Jin, J., ... Miskimins, W. K. (2019). Use of antimetastatic SOD3-mimetic albumin as a primer in triple negative breast cancer. Journal of Oncology, 2019, [3253696]. https://doi.org/10.1155/2019/3253696

Use of antimetastatic SOD3-mimetic albumin as a primer in triple negative breast cancer. / Messerli, Shanta M.; Schaefer, Amanda M.; Zhuang, Yongxian; Soltys, Bohdan J.; Keime, Noah; Jin, Jenny; Ma, Li; Hsia, Carleton J.C.; Miskimins, W. Keith.

In: Journal of Oncology, Vol. 2019, 3253696, 01.01.2019.

Research output: Contribution to journalArticle

Messerli, SM, Schaefer, AM, Zhuang, Y, Soltys, BJ, Keime, N, Jin, J, Ma, L, Hsia, CJC & Miskimins, WK 2019, 'Use of antimetastatic SOD3-mimetic albumin as a primer in triple negative breast cancer', Journal of Oncology, vol. 2019, 3253696. https://doi.org/10.1155/2019/3253696
Messerli, Shanta M. ; Schaefer, Amanda M. ; Zhuang, Yongxian ; Soltys, Bohdan J. ; Keime, Noah ; Jin, Jenny ; Ma, Li ; Hsia, Carleton J.C. ; Miskimins, W. Keith. / Use of antimetastatic SOD3-mimetic albumin as a primer in triple negative breast cancer. In: Journal of Oncology. 2019 ; Vol. 2019.
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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.",
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AU - Schaefer, Amanda M.

AU - Zhuang, Yongxian

AU - Soltys, Bohdan J.

AU - Keime, Noah

AU - Jin, Jenny

AU - Ma, Li

AU - Hsia, Carleton J.C.

AU - Miskimins, W. Keith

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AB - 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.

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