Antineoplastic and antiherpetic activity of spermidine catecholamide iron chelators

Bergeron, Raymond J.; Gavanaugh, Paul F.; Kline, Steven J.; Hughes, Robert G.; Elliott, Gary T.; Porter, Carl W.

doi:10.1016/0006-291x(84)90755-1

Cited by 140 publications

(56 citation statements)

References 19 publications

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“…There are a number of microbial secondary metabolites containing the catecholate group(s), and many of them are classified as siderophores which function in the producing microorganism to acquire ferric ions from the environment. In addition to the ironchelating activity, some of the catecholate-containing metabolites are reported to have antiviral, antibacterial, and cytotoxic activities [11,12]. However, the anti-invasive activity of this class of compounds has not been reported.…”

Section: Bioactivitymentioning

confidence: 99%

Absolute Configuration and Antitumor Activity of Myxochelin A Produced by Nonomuraea pusilla TP-A0861†

et al. 2006

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In the screening of antitumor compounds from microbial secondary metabolites, myxochelin A was isolated from a culture broth of Nonomuraea pusilla TP-A0861. The absolute configuration was determined to be S by synthesizing both enantiomers from an L-or D-lysine derivative and comparing their specific rotations. Both enantiomers of myxochelin A showed remarkable inhibitory effects on the invasion of murine colon 26-L5 carcinoma cells at non-cytotoxic concentrations. Keywords myxochelin A, invasion, antitumor, Nonomuraea IntroductionTumor invasion is the major cause of treatment failure and death in cancer patients. The process of invasion into the basement membrane is a cascade of sequential complex steps, mainly consisting of tumor cell adhesion, enzymatic degradation of extracellular matrix proteins, and migration [1]. Compounds that inhibit any of these steps are expected to be candidates of anti-metastatic and/or anti-invasive agents. Hence, the clinical efficacy of such invasive inhibitors in cancer chemotherapy are extensively exploited [2,3].In the screening for anti-invasive compounds from natural products, myxochelin A (1) was found to inhibit the in vitro tumor cell invasion. Herein, we describe the isolation, structure determination, synthesis and biological properties of 1. Results and Discussion Screening and Structure DeterminationThe screening method employed in this study is based on the experimental model of tumor cell invasion using Transwell cell culture chamber and Matrigel, the reconstituted basement membrane [4]. This bioassay enables the detection of compounds that inhibit cell adhesion, enzymatic degradation of extracellular matrix, or migration. While screening for anti-invasive compounds from our natural products library, significant activity was shown by myxochelin A (1, Fig. 1

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Section: Bioactivitymentioning

confidence: 99%

Absolute Configuration and Antitumor Activity of Myxochelin A Produced by Nonomuraea pusilla TP-A0861†

et al. 2006

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“…Alternatively these effects [11,12] may be due to a slow in- Table 1 Physicochemical properties of the chelators The incubation of omadine with iron markedly increased its cytotoxic effects in contrast to the lipophilic spermidine catecholamide chelators which were also shown to be cytotoxic in culture but for which the effects are reversed by iron [14]. The difference may be related to the inability of the spermidine catecholamide chelator-iron complexes to diffuse across the cell membrane due to their larger size.…”

Section: Inhibition Of [3h]tdr Uptakementioning

confidence: 99%

“…Effective iron chelators like desferrioxamine may inhibit the toxicity of iron in vitro, but less effective ones like EDTA may exacerbate its toxic effects [9,10] Desferrioxamine has been reported to inhibit DNA synthesis in a variety of cell culture systems, although the effect has only been seen at high drug concentrations or with prolonged exposure of the cells to the drug [ 1 l-131. Other potential iron chelating drugs may be more effective in inhibiting DNA synthesis [7,11], and some have been reported to be cytotoxic [ 11,14,15]. …”

Section: Introductionmentioning

confidence: 99%

Cytotoxic effects of the lipophilic iron chelator omadine

1986

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Cytotoxic effects were observed following 4 h incubation of human leukaemic cells with the iron chelator 1‐hydroxypyridine‐2‐thione (omadine). Its Cytotoxic activity was comparable to that of the cytotoxic drug doxorubicin. At the same concentration two other effective iron chelators, desferrioxamine and 1,2‐dimethyl‐3‐hydroxypyrid‐4‐one, were not cytotoxic. Addition of iron augmented the effect of omadine. It is suggested that the lipophilic properties of omadine and of its iron complex cause their intracellular accumulation and potent cytotoxic activity.

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“…[1][2][3][4][5] The ability of these ligands to inhibit growth reflects the importance of Fe in crucial metabolic pathways, including DNA synthesis and adenosine triphosphate production. 6,7 Numerous cancer cell types are more susceptible to the effects of chelators than normal cells.…”

Section: Introductionmentioning

confidence: 99%

The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents, IV: the mechanisms involved in inhibiting cell-cycle progression

Gao

Richardson

2001

Blood

212

234

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Some chelators of the pyridoxal isonicotinoyl hydrazone class have antiproliferative activity that is far greater than desferrioxamine (DFO). In this study, DFO was compared with one of the most active chelators (311) on the expression of molecules that play key roles in cell-cycle control. This was vital for understanding the role of iron (Fe) in cell-cycle progression and for designing chelators to treat cancer. Incubating cells with DFO, and especially 311, resulted in a decrease in the hyperphosphorylated form of the retinoblastoma susceptibility gene product (pRb). Chelators also decreased cyclins D1, D2, and D3, which bind with cyclindependent kinase 4 (cdk4) to phosphorylate pRb. The levels of cdk2 also decreased after incubation with DFO, and especially 311, which may be important for explaining the decrease in hyperphosphorylated pRb. Cyclins A and B1 were also decreased after incubation with 311 and, to a lesser extent, DFO. In contrast, cyclin E levels increased. These effects were prevented by presaturating the chelators with Fe. In contrast to DFO and 311, the ribonucleotide reductase inhibitor hydroxyurea increased the expression of all cyclins. Hence, the effect of chelators on cyclin expression was not due to their ability to inhibit ribonucleotide reductase. Although chelators induced a marked increase in WAF1 and GADD45 mRNA transcripts, there was no appreciable increase in their protein levels. Failure to translate these cell-cycle inhibitors may contribute to dysregulation of the cell cycle after exposure to chelators. IntroductionMany studies have demonstrated that some tumor cells are sensitive to iron (Fe) chelation therapy. [1][2][3][4][5] The ability of these ligands to inhibit growth reflects the importance of Fe in crucial metabolic pathways, including DNA synthesis and adenosine triphosphate production. 6,7 Numerous cancer cell types are more susceptible to the effects of chelators than normal cells. [6][7][8][9][10] Indeed, a series of studies has demonstrated that the clinically used chelator, desferrioxamine (DFO; Figure 1), is capable of a potent cytotoxic effect on neuroblastoma (NB) cells both in vitro and in clinical trials. [11][12][13][14][15] However, DFO has some serious disadvantages, including high cost, short plasma half-life, poor absorption from the gut, limited membrane permeability, and long subcutaneous administration (12-24 hours a day, 5-6 times a week). 7 Hence, further studies are necessary to develop more effective ligands as anticancer agents.Some chelators of the PIH class show high antiproliferative activity. 7,16 These compounds have high affinity and specificity for Fe similar to that of DFO and much greater than that of EDTA. 17 We have characterized PIH analogues of the 2-hydroxy-1-naphthylaldehyde group that show much greater antiproliferative activity than DFO. [18][19][20][21] In fact, their activity was comparable to bleomycin and cisplatin. 19 Our studies have shown that their ability to chelate intracellular Fe is the reason for the cytotoxic effe...

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Antineoplastic and antiherpetic activity of spermidine catecholamide iron chelators

Cited by 140 publications

References 19 publications

Absolute Configuration and Antitumor Activity of Myxochelin A Produced by Nonomuraea pusilla TP-A0861†

Absolute Configuration and Antitumor Activity of Myxochelin A Produced by Nonomuraea pusilla TP-A0861†

Cytotoxic effects of the lipophilic iron chelator omadine

The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents, IV: the mechanisms involved in inhibiting cell-cycle progression

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