Combined administration of EGCG and IL-1 receptor antagonist efficiently             downregulates IL-1-induced tumorigenic factors in U-2 OS human osteosarcoma cells.
Chronic inflammation represents one of the hallmarks of cancer. Of special relevance to the malignant process is the pro-inflammatory cytokine IL-1 playing a crucial role in cancer-related inflammation. Recent observations indicate increased IL-1 levels in an animal model of human osteosarcoma, the most frequent primary malignant bone tumor in man. In patients with bone sarcomas, increased serum levels of tumor-promoting cytokines, including IL-6, IL-8 and VEGF can be found, correlating with poor overall survival. The link between cancer and inflammation makes it clear that there is a need to reduce the external factors inducing inflammation as a preventive or therapeutical measure. Therefore, in the present study the effects of anti-inflammatory IL-1 receptor antagonist (IL-1Ra) was tested alone and in combination with (-)-epigallocatechin-3-gallate (EGCG), an anti-inflammatory chemopreventive agent from green tea, on the production of IL-1-induced tumorigenic factors in U-2 OS human osteosarcoma cells. We found that IL-1Ra and EGCG downregulated IL-1-induced IL-6 and IL-8 release from U-2 OS cells by 65-85%. IL-1Ra and EGCG also reduced secretion of invasiveness-promoting MMP-2 and pro-angiogenic VEGF to 62-75% without affecting the metabolic response and caspase-3 activity. In conclusion, downregulation of IL-1-induced tumorigenic factors (IL-6, IL-8, VEGF, MMP-2) in U-2 OS by IL-1Ra and EGCG may positively affect tumor-associated inflammation and, as a consequence, lead to reduction in angiogenesis and invasiveness. This renders a combined administration of EGCG and IL-1Ra a promising approach as an adjuvant therapy in patients with osteosarcoma.
Department of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald, Germany.
Anne-Sophie
AS
Hönicke
Stephan Albrecht
SA
Ender
Jürgen
J
Radons
D000970:Antineoplastic Agents / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D004357:Drug Synergism; D004789:Enzyme Activation; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology*; D007375:Interleukin-1 / Q000502:physiology*; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D012516:Osteosarcoma / Q000188:drug therapy*; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000970:Antineoplastic Agents; C508600:IL6 protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D017472:Receptors, Interleukin-1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D002392:Catechin; C045651:epigallocatechin gallate; C505407:CASP3 protein, human; D053148:Caspase 3; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2