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

• Published in: PloS one Vol. 12; no. 6; p. e0178830
• Main Authors: Borin, Thaiz F, Shankar, Adarsh, Angara, Kartik, Rashid, Mohammad H, Jain, Meenu, Iskander, Asm, Ara, Roxan, Lebedyeva, Iryna, Korkaya, Hasan, Achyut, Bhagelu R, Arbab, Ali S
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 13-06-2017; Public Library of Science (PLoS)
• Subjects: 1-Phosphatidylinositol 3-kinase; Administration, Intravenous; AKT protein; Amidines - administration & dosage; Amidines - pharmacology; Animals; Biology and Life Sciences; Blood; Blotting, Western; Bone imaging; Bone marrow; Breast cancer; Cadherins - metabolism; Cancer; Cancer metastasis; Cell cycle; Cell Line, Tumor; Cell Movement - drug effects; Chemokines; Cytokines; Cytokines - metabolism; Cytometry; Death; Disease Models, Animal; Female; Flow cytometry; Genetic aspects; Growth factors; Humans; Imaging; Immunocompetence; Immunohistochemistry; Immunosuppression; Inflammation; Inflammation Mediators - metabolism; Inhibitors; Invasiveness; Kinases; Lung cancer; Lung Neoplasms - metabolism; Lung Neoplasms - prevention & control; Lung Neoplasms - secondary; Lungs; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; Mathematical models; Medical prognosis; Medicine and Health Sciences; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinases - metabolism; Mortality; Penicillin; Populations; Releasing; Research and Analysis Methods; Spleen; Surgical implants; Tumor Burden - drug effects; Tumor cells; Tumor Microenvironment - drug effects; Tumor necrosis factor; Tumor necrosis factor-TNF; Tumors; Vascular endothelial growth factor; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0178830

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 (HPßCD-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 myeloid-derived suppressive cells (MDSCs) populations and endothelial phenotype. Tumor and lungs were collected for protein analysis. Our results show that HPßCD-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 HPßCD-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, HPßCD-HET0016 showed potential in treating lung metastasis in a preclinical mouse model and needs further investigations on TME.