Porshneva Kseniia, Papiernik Diana, Psurski Mateusz, Łupicka-Słowik Agnieszka, Matkowski Rafał, Ekiert Marcin, Nowak Marcin, Jarosz Joanna, Banach Joanna, Milczarek Magdalena, Goszczyński Tomasz M, Sieńczyk Marcin, Wietrzyk Joanna
Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland.
Faculty of Chemistry, Division of Medicinal Chemistry and Microbiology, Wroclaw University of Science and Technology, Wroclaw, Poland.
Theranostics. 2019 May 31;9(13):3918-3939. doi: 10.7150/thno.31461. eCollection 2019.
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). : Mice injected intravenously with 4T1-luc2-tdTomato or orthotopically with 4T1 mouse mammary gland cancer cells were treated with CORM-A1 and DETA/NO. 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 . : 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 and inhibited aggregation as well as TGF-β release from breast cancer patients' platelets . 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. : 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.
一氧化碳和一氧化氮是两种最重要的血管保护介质。在与癌症进展相关的血管功能障碍期间观察到它们的下调,这会导致血小板不受控制的活化。因此,我们研究的目的是通过同时使用CO和NO供体(分别为CORM-A1和DETA/NO)来改善血管保护并减少小鼠乳腺癌进展过程中的血小板活化。给静脉注射4T1-luc2-tdTomato或原位注射4T1小鼠乳腺癌细胞的小鼠用CORM-A1和DETA/NO进行治疗。在健康供体和乳腺癌患者的血液中评估血小板的聚集和活化。此外,我们分析了这些化合物对4T1小鼠和MDA-MB-231人乳腺癌细胞增殖、黏附和迁移的直接作用。我们观察到联合治疗的抗转移作用,在原位模型中只是短暂的。在肿瘤进展的早期阶段,同时使用CORM-A1和DETA/NO显示出血管保护能力(降低血浆中内皮素-1、sICAM和sE-选择素水平),下调血小板活化(降低纤维蛋白原和vWf与血小板的结合)以及抑制EMT过程。CO和NO供体的联合治疗减少了乳腺癌细胞的黏附和迁移,并抑制了乳腺癌患者血小板的聚集以及TGF-β释放。然而,在肿瘤进展的后期未观察到抗转移作用,此时伴随着血小板活化增加和与VASP水平降低相关的内皮功能障碍。该治疗显示出具有抗转移作用,并导致内皮代谢正常化、血小板活化减少和EMT过程受到抑制。在肿瘤播散的早期阶段,这种作用更为显著。这种治疗可应用于在该过程的第一阶段抑制转移。