Desferrithiocin is a more potent antineoplastic agent than desferrioxamine

Abstract

Desferrithiocin (DFT) is an orally e ective Fe chelator, with a similar high a nity and selectivity for Fe to desferrioxamine (DFO), which has been shown clinically to possess antineoplastic activity. In this study, DFT was assessed for antineoplastic potential in hepatocellular carcinoma cell lines (HCC). This was done as there are few treatments for this aggressive neoplasm. The e ects of DFT on cell proliferation, cell cycle progression, Fe uptake and toxicity were examined. To establish whether DFT was selective for cancer cells a comparison was made with normal (non-proliferating) hepatocytes and non-tumorigenic (proliferating) ®broblasts (SWISS-3T3). DFT was a potent inhibitor of HCC proliferation (IC 50 *40 mM). DFO also inhibited HCC proliferation under the same conditions, but was much less active (IC 50 =110 ± 210 mM). When saturated with Fe, the activity of DFT, like DFO, was greatly diminished, suggesting it may act by depriving the cells of Fe or inactivating essential Fe pool(s). Indeed DFT rapidly decreased Fe uptake from Tf-59 Fe by hepatoma cells and also by normal hepatocytes. However, DFT (and DFO) had much less e ect on cell survival in hepatocytes and ®broblasts than in hepatoma cells. DFT may, like DFO, inhibit the cell cycle in the S phase of DNA synthesis. Both chelators showed low toxicity. These results indicate that DFT has potent antineoplastic activity in HCC. Further investigation into the DFT class of Fe chelators seems warranted, particularly in view of its high activity in relation to DFO, a chelator which is already in clinical trial for neuroblastoma.

Novel di-2-pyridyl–derived iron chelators with marked and selective antitumor activity: in vitro and in vivo assessment

“…The antiproliferative activity of some of these chelators (eg, Dp44mT) was greater than ligands previously characterized by others [25][26][27][28] and our laboratory. [7][8][9]23,24 Indeed, their activity was greater than that of 311 and 3-AP and was similar to that of doxorubicin (Table 1).…”

“…[1][2][3][4][5][6][7][8][9][10][11] This sensitivity probably exists because cancer cells have greater Fe requirements than their normal counterparts [12][13][14][15] and because cancer cells express higher levels of the Fe-containing enzyme, ribonucleotide reductase (RR), which is the critical rate-limiting step in DNA synthesis. [16][17][18][19][20][21] Many in vitro 2,4,[7][8][9][21][22][23][24][25][26][27][28] and in vivo 6,29,30 studies and clinical trials 3,5,[31][32][33][34][35][36] have demonstrated that chelators are effective antiproliferative agents (for reviews, see Hershko,10 Lovejoy and Richardson, 11 and Richardson 37 ). The most well-studied chelator is desferrioxamine (DFO; …”

The Evolution of Iron Chelators for the Treatment of Iron Overload Disease and Cancer

“…Desferrithiocin as a selective antiproliferative agent. Although the studies on DFT described above mainly concentrated on the efficacy of the chelator for the treatment of iron overload disease, several studies have assessed the antiproliferative activity of this ligand in vitro (Kicic et al, 2001b(Kicic et al, , 2002. These investigations showed that DFT was more effective than DFO at inhibiting proliferation (IC 50 ϭ 40 M) although its activity was far less than that of other chelators in current development, for example, those of the di-2-pyridylketone thiosemicarbazone (DpT) class for which IC 50 values of 0.03 M were reported ) (see section VI.B.5.c.).…”

3-Hidroksipiridin-4-oni (II. dio): Biološka primjena kao kelatora željeza

“…In vitro i klinička istraživanja 34,35 pokazala su da su agresivni tumori poput leukemije vrlo osjetljivi na terapiju keliranja željeza s pomoću DFO-a. Dokazano je da se njegovo antiproliferativno djelovanje ispoljava osiromašivanjem stanice željezom i na taj način inhibira enzim RR.…”