Binding of transferrin‐iron by adriamycin at acidic pH

Abstract

It is shown that adriamycin is able to chelate iron released from iron-loaded serum transferrin in the pH range from 6.54.1. The kinetics of iron transfer to free adriamycin and to adriamycin covalently attached to the transferrin has been determined. The results show that adriamycin, if introduced into intracellular acidic compa~ments, could function as acceptor for transferrin-iron.Adriamycin Transferrin (Human serum) Adriamycin-Fe3+ complex

The removal of metal ions from transferrin, ferritin and ceruloplasmin by the cardioprotective agent ICRF-187 [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane] and its hydrolysis product ADR-925

“…Experiments were also carried out to see if ICRF-198 could remove Fe 3 + from the Fe 3+-doxOrubicin complex formed from iron released from transferrin. Thus, as previously described [29], a slow increase in absorbance at 600nm due to the formation of the Fe 3 +-doxorubicin complex was observed at pH 5.5 in the presence of transferrin (15 laM Fe 3+) and 100 gM doxorubicin. Upon the addition of either 50 or 100 p.M ICRF-198 at 12 min, the absorbance decreased with a half-time of about 2 min, indicative of the complete removal of iron from the Fe 3 +-doxorubicin complex, as might be expected from previous studies [18,19].…”

“…If ICRF-187 is able to enter the low pH vesicle and undergo hydrolysis to ADR-925, it would then be able to remove iron from transferrin. Doxorubicin has been shown to remove iron from transferrin at acid pH [29] at rates similar to those observed for ICRF-198 and ADR-925. Given the fact that ADR-925 is able to remove iron from the Fe3+-doxorubicin complex [18,19], ADR-925 would be able to remove any transferrin-derived iron complexed to doxorubicin.…”

“…ICRF-187 has also been shown in animal models to reduce bleomycin-induced pulmonary toxicity [24], isoproterenol-induced cardiotoxicity [25], acetaminophen-induced hepatotoxicity [26], and alloxan-induced diabetes [27], thus implicating iron-based oxygen radical damage in these toxicities as well. It has been shown that the iron-storage protein ferritin slowly releases its iron to doxorubicin [28] and that even the strongly bound iron of the iron transport protein transferrin can, at acid pH, give up its iron to doxorubicin [29]. It was also demonstrated by Thomas and Aust [30] that in the presence of NADPH-cytochrome P-450 reductase, doxorubicin mediates a slow reductive release of iron from ferritin.…”

Anthracyclines Induce Accumulation of Iron in Ferritin in Myocardial and Neoplastic Cells: Inhibition of the Ferritin Iron Mobilization Pathway

“…The IRPs are involved in post-translational regulation of various molecules involved in Fe metabolism, including ferritin and the TfR1 (Hentze and Kü hn, 1996;Richardson and Ponka, 1997). Several studies in vitro have also assessed the ability of anthracyclines to mobilize Fe from purified ferritin (Demant, 1984;Thomas and Aust, 1986;Gianni and Myers, 1992), Tf (Demant and Norskov-Lauritsen, 1986), and microsomal membranes (Minotti, 1990;Gianni and Myers, 1992). However, it is difficult to determine whether the Fe release observed from isolated and purified ferritin is physiologically relevant.…”

The iron(III)-adriamycin complex inhibits cytochrome c oxidase before its inactivation

“…The pentan-1-ol protection experiments demonstrate that this is indeed the case. It has previously been demonstrated (Demant & Norskov-Lauritsen, 1986) that the strongly bound iron of the iron-transport protein transferrin can be transferred to adriamycin. Thus the Fe3+-adriamycin species may be formed in vivo.…”