Cytotoxicity of vacuolar H(+)-ATPase inhibitors to UMR-106 rat osteoblasts: an effect on iron uptake into cells?
Treatment of rat osteoblastic UMR-106 cells with bafilomycin A1 rhamnoside or concanamycin A, which are potent and specific inhibitors of the vacuolar H(+)-ATPase (V-ATPase), caused a rapid rounding up of the cells (within 6 hr), inhibition of cell growth (IC50 = 3.3 nM and 0.5 nM, respectively, at 24 hr) and cell death at 54 hr. Since proliferating cells have an absolute requirement for iron and the V-ATPase plays a crucial role in iron uptake into cells via the transferrin cycle, the effect of the iron chelator, desferal, was tested on UMR-106 cells. A time-dependent cell rounding, suppression of cell growth followed by cell death very similar to that observed with the V-ATPase inhibitors was seen. Therefore, the in vitro and in vivo toxicity of V-ATPase inhibitors may be due, at least in part, to their preventing iron uptake into cells.
Hall
T J
TJ
Ciba-Geigy Ltd., Research Department, Basel, Switzerland.
D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D000935:Antifungal Agents / Q000633:toxicity*; D016923:Cell Death; D002455:Cell Division; D002460:Cell Line; D003676:Deferoxamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007501:Iron / Q000493:pharmacokinetics*; D018942:Macrolides; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism*; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors*; D051381:Rats; D013997:Time Factors
D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D018942:Macrolides; C036978:concanamycin A; C040929:bafilomycin A1; D007501:Iron; D006180:Proton-Translocating ATPases; D003676:Deferoxamine