Apigenin and Luteolin Attenuate the Breaching of MDA-MB231 Breast Cancer Spheroids Through the Lymph Endothelial Barrier
| Autor: | Junli Hong, Adryan Fristiohady, Chi H. Nguyen, Daniela Milovanovic, Nicole Huttary, Sigurd Krieger, Junqiang Hong, Silvana Geleff, Peter Birner, Walter Jäger, Ali Özmen, Liselotte Krenn, Georg Krupitza |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
3D model CYP1A1 03 medical and health sciences chemistry.chemical_compound Ca2+ release 0302 clinical medicine Breast cancer In vivo medicine Pharmacology (medical) Original Research Pharmacology FAK Chemistry intravasation lcsh:RM1-950 fungi Intravasation Transfection medicine.disease Endothelial stem cell lcsh:Therapeutics. Pharmacology 030104 developmental biology 030220 oncology & carcinogenesis Cancer cell Apigenin flavonoids Cancer research MMP1 Luteolin |
| Zdroj: | Frontiers in Pharmacology Frontiers in Pharmacology, Vol 9 (2018) |
| ISSN: | 1663-9812 |
| Popis: | Flavonoids, present in fruits, vegetables and traditional medicinal plants, show anticancer effects in experimental systems and are reportedly non-toxic. This is a favorable property for long term strategies for the attenuation of lymph node metastasis, which may effectively improve the prognostic states in breast cancer. Hence, we studied two flavonoids, apigenin and luteolin exhibiting strong bio-activity in various test systems in cancer research and are readily available on the market. This study has further advanced the mechanistic understanding of breast cancer intravasation through the lymphatic barrier. Apigenin and luteolin were tested in a three-dimensional (3-D) assay consisting of MDA-MB231 breast cancer spheroids and immortalized lymph endothelial cell (LEC) monolayers. The 3-D model faithfully resembles the intravasation of breast cancer emboli through the lymphatic vasculature. Western blot analysis, intracellular Ca2+ determination, EROD assay and siRNA transfection revealed insights into mechanisms of intravasation as well as the anti-intravasative outcome of flavonoid action. Both flavonoids suppressed pro-intravasative trigger factors in MDA-MB231 breast cancer cells, specifically MMP1 expression and CYP1A1 activity. A pro-intravasative contribution of FAK expression in LECs was established as FAK supported the retraction of the LEC monolayer upon contact with cancer cells thereby enabling them to cross the endothelial barrier. As mechanistic basis, MMP1 caused the phosphorylation (activation) of FAK at Tyr397 in LECs. Apigenin and luteolin prevented MMP1-induced FAK activation, but not constitutive FAK phosphorylation. Luteolin, unlike apigenin, inhibited MMP1-induced Ca2+ release. Free intracellular Ca2+ is a central signal amplifier triggering LEC retraction through activation of the mobility protein MLC2, thereby enhancing intravasation. FAK activity and Ca2+ levels did not correlate. This implicates that the pro-intravasative contribution of FAK and of Ca2+ release in LECs was independent of each other and explains the better anti-intravasative effects of luteolin in vitro. In specific formulations, flavonoid concentrations causing significant anti-intravasative effects, can certainly be achieved in vivo. As the therapeutic strategy has to be based on permanent flavonoid treatment both the beneficial and adverse effects have to be investigated in future studies. |
| Databáze: | OpenAIRE |
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