Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases

Casero, Robert A.; Marton, Laurence J.

doi:10.1038/nrd2243

Cited by 666 publications

(738 citation statements)

References 213 publications

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“…The frequent dysregulation of polyamine metabolism in tumor cells make polyamine metabolism and function a rational target for antineoplastic therapy [20,46,47,50,51]. Although inhibitors of virtually all of the biosynthetic enzymes in polyamine metabolism have been synthesized, none has demonstrated clinical efficacy as a single agent in clinical trails for cancer (see [20]).…”

Section: Discussionmentioning

confidence: 99%

“…Although inhibitors of virtually all of the biosynthetic enzymes in polyamine metabolism have been synthesized, none has demonstrated clinical efficacy as a single agent in clinical trails for cancer (see [20]). In an attempt to overcome the limitations encountered with specific inhibitors of enzyme function, we and others have exploited the self-regulatory properties of polyamine metabolism for therapeutic advantage through the use of structural analogues of the natural polyamines [4,5,8,18,39,43,44,49].…”

Section: Discussionmentioning

confidence: 99%

“…Several classes of polyamine analogues alter polyamine metabolism through multiple regulatory pathways [20]. The original basis for the synthesis of polyamine analogues for the treatment of cancer was based on the self-regulating nature of polyamine metabolism [39,40].…”

Section: Effects Of Cgc-11047 On Polyamine Metabolismmentioning

confidence: 99%

“…Polyamine concentrations are increased and polyamine metabolism dysregulated in multiple tumor cell types, thus making this pathway a rational target for antineoplastic therapies [10,20,28,34]. Targeting the key enzymes involved in the polyamine biosynthetic pathway, ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC) has been demonstrated to be successful as a means of targeting polyamines and regulating cell growth, but has had limited clinical success [2,33,38].…”

Section: Introductionmentioning

confidence: 99%

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In vitro and in vivo effects of the conformationally restricted polyamine analogue CGC-11047 on small cell and non-small cell lung cancer cells

Hacker

Marton²,

Sobolewski

et al. 2008

Cancer Chemother Pharmacol

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Purpose-Polyamines are essential for normal growth; however, the requirement for, and the metabolism of, polyamines are frequently dysregulated in cancer. Polyamine analogues have demonstrated promising preclinical results in multiple model systems of cancer, but their clinical utility has been limited by apparent toxicity. A representative compound of a new generation of short chain, conformationally restricted polyamine analogues, CGC-11047 has been synthesized and ongoing phase I clinical trials indicate it to be well tolerated at weekly doses of 610 mg (dose escalation is still in progress). Therefore, studies were designed to gain a better understanding of its effects on cellular polyamine biochemistry and efficacy in the treatment of human lung cancer models in vitro and in vivo.Methods-Human lung cancers cell lines representing non-small cell and small cell lung cancers were investigated for their growth and biochemical response to CGC-11047. Effects of in vitro treatment with CGC-11047 on cell growth, the activity of the polyamine biosynthetic enzyme ornithine decarboxylase (ODC), and the expression and activity of the polyamine catabolic enzymes spermidine/spermine N 1 -acetyltransferase (SSAT) and spermine oxides (SMO) were measured. Additionally, the overall effects on intracellular polyamine pools were monitored. Finally, the in vivo efficacy of CGC-11047 in the treatment of a nude mouse model of human nonsmall cell lung cancer was evaluated.Results-CGC-11047 effectively inhibited the growth of both small cell and non-small cell lung cancer cells in vitro. The greatest biochemical effects were observed in the non-small cell lung cancer cells where in addition to a profound down regulation of ODC activity, there was a significant increase in polyamine catabolism leading to a greater degree of polyamine pool depletion and greater accumulation of CGC-11047 when compared with the changes observed for

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Effects Of Cgc-11047 On Polyamine Metabolismmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

In vitro and in vivo effects of the conformationally restricted polyamine analogue CGC-11047 on small cell and non-small cell lung cancer cells

Hacker

Marton²,

Sobolewski

et al. 2008

Cancer Chemother Pharmacol

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“…[1][2][3][4][5][6][7] Spermidine is a major polyamine that serves multiple functions in growth including its role as a precursor of hypusine, which is essential for the activity of the eukaryotic initiation factor elF-5A. [8][9][10][11] Polyamines are formed in eukaryotes and in many, but not all, prokaryotes by the action of aminopropyltransferases.…”

Section: Introductionmentioning

confidence: 99%

Binding and inhibition of human spermidine synthase by decarboxylated S‐adenosylhomocysteine

Šečkutė¹,

McCloskey²,

Thomas³

et al. 2011

Protein Science

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Aminopropyltransferases are essential enzymes that form polyamines in eukaryotic and most prokaryotic cells. Spermidine synthase (SpdS) is one of the most well-studied enzymes in this biosynthetic pathway. The enzyme uses decarboxylated S-adenosylmethionine and a short-chain polyamine (putrescine) to make a medium-chain polyamine (spermidine) and 5 0 -deoxy-5 0 -methylthioadenosine as a byproduct. Here, we report a new spermidine synthase inhibitor, decarboxylated S-adenosylhomocysteine (dcSAH). The inhibitor was synthesized, and dosedependent inhibition of human, Thermatoga maritima, and Plasmodium falciparum spermidine synthases, as well as functionally homologous human spermine synthase, was determined. The human SpdS/dcSAH complex structure was determined by X-ray crystallography at 2.0 Å resolution and showed consistent active site positioning and coordination with previously known structures. Isothermal calorimetry binding assays confirmed inhibitor binding to human SpdS with K d of 1.1 6 0.3 lM in the absence of putrescine and 3.2 6 0.1 lM in the presence of putrescine. These results indicate a potential for further inhibitor development based on the dcSAH scaffold.

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Cysteine is a limiting factor for glioma proliferation and survival

et al. 2022

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Nutritional intervention is becoming more prevalent as adjuvant therapy for many cancers in view of the tumor dependence on external sources for some nutrients. However, little is known about the mechanisms that make cancer cells require certain nutrients from the microenvironment. Herein, we report the dependence of glioma cells on exogenous cysteine/cystine, despite this amino acid being nonessential. Using several 13C‐tracers and analysis of cystathionine synthase and cystathioninase levels, we revealed that glioma cells were not able to support glutathione synthesis through the transsulfuration pathway, which allows methionine to be converted to cysteine in cysteine/cystine‐deprived conditions. Therefore, we explored the nutritional deprivation in a mouse model of glioma. Animals subjected to a cysteine/cystine‐free diet survived longer, although this increase did not attain statistical significance, with concomitant reductions in plasma glutathione and cysteine levels. At the end point, however, tumors displayed the ability to synthesize glutathione, even though higher levels of oxidative stress were detected. We observed a compensation from the nutritional intervention revealed as the recovery of cysteine‐related metabolite levels in plasma. Our study highlights a time window where cysteine deprivation can be exploited for additional therapeutic strategies.

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Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases

Cited by 666 publications

References 213 publications

In vitro and in vivo effects of the conformationally restricted polyamine analogue CGC-11047 on small cell and non-small cell lung cancer cells

In vitro and in vivo effects of the conformationally restricted polyamine analogue CGC-11047 on small cell and non-small cell lung cancer cells

Binding and inhibition of human spermidine synthase by decarboxylated S‐adenosylhomocysteine

Cysteine is a limiting factor for glioma proliferation and survival

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