Temporal inhibition of mouse mammary gland cancer metastasis by CORM-A1 and DETA/NO combination therapy

Abstract

Carbon monoxide and nitric oxide are two of the most important vasoprotective mediators. Their downregulation observed during vascular dysfunction, which is associated with cancer progression, leads to uncontrolled platelet activation. Therefore, the aim of our studies was to improve vasoprotection and to decrease platelet activation during progression of mouse mammary gland cancer by concurrent use of CO and NO donors (CORM-A1 and DETA/NO, respectively). Methods : Mice injected intravenously with 4T1-luc2-tdTomato or orthotopically with 4T1 mouse mammary gland cancer cells were treated with CORM-A1 and DETA/NO. Ex vivo aggregation and activation of platelets were assessed in the blood of healthy donors and breast cancer patients. Moreover, we analyzed the compounds' direct effect on 4T1 mouse and MDA-MB-231 human breast cancer cells proliferation, adhesion and migration in vitro . Results : We have observed antimetastatic effect of combination therapy, which was only transient in orthotopic model. During early stages of tumor progression concurrent use of CORM-A1 and DETA/NO demonstrated vasoprotective ability (decreased endothelin-1, sICAM and sE-selectin plasma level) and downregulated platelets activation (decreased bound of fibrinogen and vWf to platelets) as well as inhibited EMT process. Combined treatment with CO and NO donors diminished adhesion and migration of breast cancer cells in vitro and inhibited aggregation as well as TGF-β release from breast cancer patients' platelets ex vivo . However, antimetastatic effect was not observed at a later stage of tumor progression which was accompanied by increased platelets activation and endothelial dysfunction related to a decrease of VASP level. Conclusion : The therapy was shown to have antimetastatic action and resulted in normalization of endothelial metabolism, diminution of platelet activation and inhibition of EMT process. The effect was more prominent during early stages of tumor dissemination. Such treatment could be applied to inhibit metastasis during the first stages of this process.

Retinol-Binding Protein 4 Accelerates Metastatic Spread and Increases Impairment of Blood Flow in Mouse Mammary Gland Tumors

“…Tumor blood perfusion analysis was performed using intravenous injection of MicroMarker TM Contrast Agent by the Vevo2100 ultrasound imaging system (VisualSonics, Ontario, Canada) as described previously [10]. The analysis of the received data was carried out using the VevoLab and VevoCQ software (VisualSonics).…”

“…These processes precede the onset of a phenotypic switch in the lung endothelium toward a mesenchymal phenotype (EndMT), which is parallel to the appearance of the first pulmonary metastatic colonies [7]. Therefore, therapeutic strategies that aim to normalize endothelial dysfunction can decrease the metastatic potential of this type of breast cancer [8][9][10].Apart from its involvement in cancer development, endothelial dysfunction plays an important role in the development of cardiovascular diseases and atherosclerosis. Moreover, in type 2 diabetes mellitus, endothelial dysfunction and insulin resistance often coexist at the earliest stage of atherosclerosis with elevation of serum retinol-binding protein 4 (RBP4), a specific retinol transporter in the blood [11].…”

“…These processes precede the onset of a phenotypic switch in the lung endothelium toward a mesenchymal phenotype (EndMT), which is parallel to the appearance of the first pulmonary metastatic colonies [7]. Therefore, therapeutic strategies that aim to normalize endothelial dysfunction can decrease the metastatic potential of this type of breast cancer [8][9][10].…”

EMT related circular RNA expression profiles identify circSCYL2 as a novel molecule in breast tumor metastasis

“…Epithelial cancer cells in the lactiferous duct having undergone EMT are capable of undergoing metastasis and are more invasive (9)(10)(11). Transforming growth factor (TGF)-β1 has been reported to induce EMT (12). The loss of epithelial (E)-cadherin, an adherens junction cell surface protein expressed in epithelial cells is the principal characteristic of EMT.…”

“…In breast cancer, EMT both elevates the migratory capacity and invasive potential of tumor cells and initiates pro-tumorigenic alterations in the tumor microenvironment (14). cORM-A1 and dETA/NO combination therapy showed antimetastatic action and resulted in normalization of endothelial metabolism, diminution of platelet activation, and inhibition of EMT progression (12). coenzyme Q 0 attributed to the phosphatidyl inositol 3 kinase (PI3K)/protein kinase B (AKT)/nuclear factor (NF)κB/matrix metalloproteinase-9 signaling pathway through reactive oxygen species-mediated apoptosis can inhibit the progression of metastasis as well as EMT (in vitro and in vivo) (15).…”