Tyrosyl DNA phosphodiesterase 2 (TDP2) facilitates the repair of topoisomerase II (TOP2)-linked DNA double-strand breaks and, as a consequence, is required for cellular resistance to TOP2 "poisons". Recently, a deazaflavin series of compounds were identified as potent inhibitors of TDP2, in vitro. Here, however, we show that while some deazaflavins can induce cellular sensitivity to the TOP2 poison etoposide, they do so independently of TDP2 status. Consistent with this, both the cellular level of etoposide-induced TOP2 cleavage complexes and the intracellular concentration of etoposide was increased by incubation with deazaflavin, suggesting an impact of these compounds on etoposide uptake/efflux. In addition, deazaflavin failed to increase the level of TOP2 cleavage complexes or sensitivity induced by m-AMSA, which is a different class of TOP2 poison to which TDP2-defective cells are also sensitive. In conclusion, while deazaflavins are potent inhibitors of TDP2 in vitro, their limited cell permeability and likely interference with etoposide influx/efflux limits their utility in cells.
- MeSH
- aza sloučeniny chemie MeSH
- biologický transport MeSH
- buněčné linie MeSH
- DNA vazebné proteiny antagonisté a inhibitory MeSH
- etoposid farmakokinetika MeSH
- flaviny chemie farmakokinetika farmakologie MeSH
- fosfodiesterasy MeSH
- inhibitory topoisomerasy II farmakokinetika MeSH
- knihovny malých molekul farmakologie MeSH
- kur domácí MeSH
- lidé MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Flavin7 (F7) is a nutritional supplement often taken by cancer patients in Central Europe during chemo- and radiation therapy. In this study, investigation of the antiproliferative and antiangiogenic activities of this supplement were performed. Flavin7 showed antiproliferative activity in Jurkat as well as in HeLa cells. It significantly reduced the growth of both cancer cell lines at the doses of 200 microg/ml to 20 microg/ml (p<0.001 and p<0.01, respectively). In F7-treated Jurkat cells we found a significant increase in the fraction of cells with sub-G(0)/G(1) DNA content, which is considered to be a marker of apoptotic cell death. Apoptosis was also confirmed by annexin V staining and DNA fragmentation. Furthermore, F7 at the doses of 100 microg/ml to 4 microg/ml inhibited endothelial cell migration and capillary tube formation what indicates its potential antiangiogenic properties. Flavin7 also inhibited the activity of matrix metalloproteinases (MMPs), preferentially MMP-9, at the doses of 100 microg/ml to 4 microg/ml. Our data suggest that F7 possesses marked antiproliferative and antiangiogenic properties in vitro. Further research is needed to elucidate also its in vivo activities.
- MeSH
- apoptóza účinky záření MeSH
- buněčný cyklus účinky léků MeSH
- endoteliální buňky enzymologie patologie účinky léků MeSH
- financování organizované MeSH
- flaviny farmakologie MeSH
- flavonoidy farmakologie MeSH
- fragmentace DNA MeSH
- fytogenní protinádorové látky farmakologie MeSH
- fyziologická neovaskularizace účinky léků MeSH
- HeLa buňky MeSH
- inhibitory angiogeneze farmakologie MeSH
- inhibitory matrixových metaloproteinas MeSH
- inhibitory proteas farmakologie MeSH
- Jurkat buňky MeSH
- lidé MeSH
- matrixová metaloproteinasa 9 MeSH
- pohyb buněk účinky léků MeSH
- potravní doplňky MeSH
- proliferace buněk účinky léků MeSH
- stilbeny farmakologie MeSH
- viabilita buněk účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé MeSH
- MeSH
- 2-aminopurin analogy a deriváty farmakologie chemie imunologie MeSH
- adenin analogy a deriváty farmakologie imunologie MeSH
- adjuvancia imunologická farmakologie MeSH
- antagonisté purinergního receptoru P1 MeSH
- chemokin CCL3 MeSH
- chemokin CCL4 MeSH
- chemokin CCL5 antagonisté a inhibitory genetika sekrece MeSH
- chinazoliny farmakologie MeSH
- dihydropyridiny farmakologie MeSH
- financování organizované MeSH
- flaviny farmakologie MeSH
- interleukin-10 antagonisté a inhibitory genetika sekrece MeSH
- kofein analogy a deriváty farmakologie MeSH
- kultivované buňky MeSH
- kyseliny fosforité farmakologie imunologie MeSH
- látky proti HIV farmakologie chemie imunologie MeSH
- lidé MeSH
- lipopolysacharidy farmakologie MeSH
- makrofágové zánětlivé proteiny genetika sekrece MeSH
- makrofágy cytologie metabolismus účinky léků MeSH
- messenger RNA genetika metabolismus MeSH
- molekulární struktura MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- purinergní receptory P1 fyziologie MeSH
- theofylin analogy a deriváty farmakologie MeSH
- TNF-alfa antagonisté a inhibitory genetika sekrece MeSH
- triazoly farmakologie MeSH
- viabilita buněk účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
