Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare, neuroendocrine tumors derived from adrenal or extra-adrenal chromaffin cells, respectively. Metastases are discovered in 3-36% of patients at the time of diagnosis. Currently, only suboptimal treatment options exist. Therefore, new therapeutic compounds targeting metastatic PHEOs/PGLs are urgently needed. Here, we investigated if anthracyclines were able to suppress the progression of metastatic PHEO. We explored their effects on experimental mouse PHEO tumor cells using in vitro and in vivo models, and demonstrated that anthracyclines, particularly idarubicin (IDA), suppressed hypoxia signaling by preventing the binding of hypoxia-inducible factor 1 and 2 (HIF-1 and HIF-2) to the hypoxia response element (HRE) sites on DNA. This resulted in reduced transcriptional activation of HIF target genes, including erythropoietin (EPO), phosphoglycerate kinase 1 (PGK1), endothelin 1 (EDN1), glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and vascular endothelial growth factor (VEGFA), which consequently inhibited the growth of metastatic PHEO. Additionally, IDA downregulated hypoxia signaling by interfering with the transcriptional activation of HIF1A and HIF2A. Furthermore, our animal model demonstrated the dose-dependent suppressive effect of IDA on metastatic PHEO growth in vivo. Our results indicate that anthracyclines are prospective candidates for inclusion in metastatic PHEO/PGL therapy, especially in patients with gene mutations involved in the hypoxia signaling pathway.

• Klíčová slova
• anthracyclines, hypoxia-inducible factors, metastatic, paraganglioma, pheochromocytoma,
• MeSH
• buňky - růstové procesy účinky léků   MeSH
• endotelin-1 genetika   metabolismus   MeSH
• erythropoetin genetika   metabolismus   MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa metabolismus   MeSH
• feochromocytom farmakoterapie   patologie   MeSH
• fosfoglycerátkinasa genetika   metabolismus   MeSH
• hypoxie farmakoterapie   patologie   MeSH
• idarubicin terapeutické užití   MeSH
• lidé MeSH
• metastázy nádorů MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory nadledvin farmakoterapie   patologie   MeSH
• protinádorové látky terapeutické užití   MeSH
• signální transdukce účinky léků   MeSH
• transkripční faktory bHLH metabolismus   MeSH
• vazba proteinů MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• endotelin-1 MeSH
• endothelial PAS domain-containing protein 1 MeSH Prohlížeč
• erythropoetin MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa MeSH
• fosfoglycerátkinasa MeSH
• Hif1a protein, mouse MeSH Prohlížeč
• idarubicin MeSH
• Pgk1 protein, mouse MeSH Prohlížeč
• protinádorové látky MeSH
• transkripční faktory bHLH MeSH

BACKGROUND: Using killed microorganisms or their parts to stimulate immunity for cancer treatment dates back to the end of 19th century. Since then, it undergone considerable development. Our novel approach binds ligands to the tumor cell surface, which stimulates tumor phagocytosis. The therapeutic effect is further amplified by simultaneous application of agonists of Toll-like receptors. We searched for ligands that induce both a strong therapeutic effect and are safe for humans. METHODS: B16-F10 murine melanoma model was used. For the stimulation of phagocytosis, mannan or N-formyl-methionyl-leucyl-phenylalanine, was covalently bound to tumor cells or attached using hydrophobic anchor. The following agonists of Toll-like receptors were studied: monophosphoryl lipid A (MPLA), imiquimod (R-837), resiquimod (R-848), poly(I:C), and heat killed Listeria monocytogenes. RESULTS: R-848 proved to be the most suitable Toll-like receptor agonist for our novel immunotherapeutic approach. In combination with covalently bound mannan, R-848 significantly reduced tumor growth. Adding poly(I:C) and L. monocytogenes resulted in complete recovery in 83% of mice and in their protection from the re-transplantation of melanoma cells. CONCLUSION: An efficient cancer treatment results from the combination of Toll-like receptor agonists and phagocytosis stimulating ligands bound to the tumor cells.

• Klíčová slova
• Cancer immunotherapy, Innate immunity, Mannan, Melanoma, Neutrophils, Phagocytosis, Resiquimod,
• MeSH
• cytokiny metabolismus   MeSH
• fagocytóza MeSH
• imidazoly farmakologie   MeSH
• imunoterapie * metody   MeSH
• infiltrace neutrofily imunologie   MeSH
• ligandy MeSH
• mannany imunologie   MeSH
• melanom experimentální MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• nádory imunologie   metabolismus   patologie   terapie   MeSH
• neutrofily imunologie   metabolismus   MeSH
• poly I-C imunologie   MeSH
• přirozená imunita * MeSH
• respirační vzplanutí imunologie   MeSH
• toll-like receptory agonisté   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytokiny MeSH
• imidazoly MeSH
• ligandy MeSH
• mannany MeSH
• poly I-C MeSH
• resiquimod MeSH Prohlížeč
• toll-like receptory MeSH