HET0016 decreases lung metastasis from breast cancer in immune-competent mouse model

Thaiz Ferraz Borin, Adarsh Shankar, Kartik Angara, Mohammad H. Rashid, Meenu Jain, Asm Iskander, Roxan Ara, Iryna Oleksandrivna Lebedyeva, Hasan Korkaya, Bhagelu Ram Achyut, Ali Syed Arbab

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Distant metastasis is the primary cause of death in the majority of the cancer types. Recently, much importance has been given to tumor microenvironment (TME) in the development of invasive malignant tumors, as well as the metastasis potential. The ability of tumor cells to modulate TME and to escape immune-mediated attack by releasing immunosuppressive cytokines has become a hallmark of breast cancer. Our study shows the effect of IV formulation of HET0016 (HPûCD-HET0016) a selective inhibitor of 20-HETE synthesis, administered intravenously in immune-competent in vivo mouse model of murine breast cancer. 4T1 luciferase positive cells were implanted to the mammary fat pad in Balb/c mice. Treatment started on day 15, and was administered for 5 days a week for 3 weeks. The development of metastasis was detected via optical imaging. Blood, spleen, lungs, bone marrow and tumor were collected for flow cytometry, to investigate changes in myeloidderived suppressive cells (MDSCs) populations and endothelial phenotype. Tumor and lungs were collected for protein analysis. Our results show that HPûCD-HET0016: (1) decreased tumor volume and lung metastasis compared to the vehicle group; (2) reduced migration and invasion of tumor cells and levels of metalloproteinases in the lungs of animals treated with HPûCD-HET0016 via PI3K/AKT pathway; and (3) decreased expression of pro-inflammatory cytokines, growth factors and granulocytic MDSCs population in the lung microenvironment in treated animals. Thus, HPûCD-HET0016 showed potential in treating lung metastasis in a preclinical mouse model and needs further investigations on TME.

Original languageEnglish (US)
Article number0178830
JournalPloS one
Volume12
Issue number6
DOIs
StatePublished - Jun 1 2017

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metastasis
breast neoplasms
Tumors
animal models
lungs
Breast Neoplasms
Neoplasm Metastasis
Lung
neoplasms
Tumor Microenvironment
Neoplasms
Cells
Cytokines
cytokines
Optical Imaging
Animals
Metalloproteases
Immunosuppressive Agents
Tumor Burden
Luciferases

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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HET0016 decreases lung metastasis from breast cancer in immune-competent mouse model. / Borin, Thaiz Ferraz; Shankar, Adarsh; Angara, Kartik; Rashid, Mohammad H.; Jain, Meenu; Iskander, Asm; Ara, Roxan; Lebedyeva, Iryna Oleksandrivna; Korkaya, Hasan; Achyut, Bhagelu Ram; Arbab, Ali Syed.

In: PloS one, Vol. 12, No. 6, 0178830, 01.06.2017.

Research output: Contribution to journalArticle

Borin, Thaiz Ferraz ; Shankar, Adarsh ; Angara, Kartik ; Rashid, Mohammad H. ; Jain, Meenu ; Iskander, Asm ; Ara, Roxan ; Lebedyeva, Iryna Oleksandrivna ; Korkaya, Hasan ; Achyut, Bhagelu Ram ; Arbab, Ali Syed. / HET0016 decreases lung metastasis from breast cancer in immune-competent mouse model. In: PloS one. 2017 ; Vol. 12, No. 6.
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abstract = "Distant metastasis is the primary cause of death in the majority of the cancer types. Recently, much importance has been given to tumor microenvironment (TME) in the development of invasive malignant tumors, as well as the metastasis potential. The ability of tumor cells to modulate TME and to escape immune-mediated attack by releasing immunosuppressive cytokines has become a hallmark of breast cancer. Our study shows the effect of IV formulation of HET0016 (HP{\^u}CD-HET0016) a selective inhibitor of 20-HETE synthesis, administered intravenously in immune-competent in vivo mouse model of murine breast cancer. 4T1 luciferase positive cells were implanted to the mammary fat pad in Balb/c mice. Treatment started on day 15, and was administered for 5 days a week for 3 weeks. The development of metastasis was detected via optical imaging. Blood, spleen, lungs, bone marrow and tumor were collected for flow cytometry, to investigate changes in myeloidderived suppressive cells (MDSCs) populations and endothelial phenotype. Tumor and lungs were collected for protein analysis. Our results show that HP{\^u}CD-HET0016: (1) decreased tumor volume and lung metastasis compared to the vehicle group; (2) reduced migration and invasion of tumor cells and levels of metalloproteinases in the lungs of animals treated with HP{\^u}CD-HET0016 via PI3K/AKT pathway; and (3) decreased expression of pro-inflammatory cytokines, growth factors and granulocytic MDSCs population in the lung microenvironment in treated animals. Thus, HP{\^u}CD-HET0016 showed potential in treating lung metastasis in a preclinical mouse model and needs further investigations on TME.",
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AU - Shankar, Adarsh

AU - Angara, Kartik

AU - Rashid, Mohammad H.

AU - Jain, Meenu

AU - Iskander, Asm

AU - Ara, Roxan

AU - Lebedyeva, Iryna Oleksandrivna

AU - Korkaya, Hasan

AU - Achyut, Bhagelu Ram

AU - Arbab, Ali Syed

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