Polyamines and cancer: old molecules, new understanding

Gerner, Eugene W.; Meyskens, Frank L.

doi:10.1038/nrc1454

Cited by 1,007 publications

(928 citation statements)

References 104 publications

(106 reference statements)

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“…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%

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: Introductionmentioning

confidence: 99%

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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“…It is involved in the Ubindependent protein degradation and small molecule transport (Gerner and Meyskens, 2004). Az expression is induced by an unusual polyamine-dependent mechanism in which a programmed þ 1 frame-shift occurs during translation of the Az mRNA leading to the expression of full-length and functional Az protein (Ivanov et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…Once expressed, Az binds and inhibits ornithine decarboxylase (ODC), a rate-limiting enzyme in polyamine biosynthesis, and targets it for degradation through Ub-independent pathway (Rom and Kahana, 1994). Increased polyamines and ODC activities are associated with many human malignancies (Gerner and Meyskens, 2004). As a negative regulator of ODC and thus polyamine levels, overexpression of Az leads to cell-cycle arrest, apoptosis (Iwata et al, 1999;Koike et al, 1999) and inhibition of tumor growth in in vivo mouse models (Feith et al, 2001;Fong et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Antizyme1 mediates AURKAIP1-dependent degradation of Aurora-A

Lim

Gopalan

2007

Oncogene

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“…Today, its role is seen in a considerably broader context, as antizyme 1 has been shown to affect the stability of several additional proteins such as cyclin D1 and Smad1 (Lin et al, 2002;Newman et al, 2004). Since elevated ODC activity is associated with most forms of human malignancies (Gerner and Meyskens, 2004), it was suggested early on that antizyme 1 may function as a tumor suppressor. Supporting this hypothesis, it has been shown that antizyme 1 overexpression leads to cell cycle arrest, apoptosis and reduced cell proliferation in vitro, (Iwata et al, 1999;Koike et al, 1999) and inhibits tumor growth in several mouse models in vivo (Iwata et al, 1999;Tsuji et al, 2001;Fong et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Antizyme, a mediator of ubiquitin-independent proteasomal degradation and its inhibitor localize to centrosomes and modulate centriole amplification

et al. 2007

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The potential tumor suppressor antizyme and its endogenous inhibitor (antizyme inhibitor, AZI) have been implicated in the ubiquitin-independent proteasomal degradation of proteins involved in cell proliferation as well as in the regulation of polyamine levels. We show here that both antizyme and AZI concentrate at centrosomes and that antizyme preferentially associates with the maternal centriole. Interestingly, alterations in the levels of these proteins have opposing effects on centrosomes. Depletion of antizyme in various cell lines and primary cells leads to centrosome overduplication, whereas overexpression of antizyme reduces numerical centrosome abnormalities. Conversely, silencing of the antizyme inhibitor, AZI, results in a decrease of numerical centrosome abnormalities, whereas overexpression of AZI leads to centrosome overduplication. We further show that the numerical centrosome abnormalities are due to daughter centriole amplification. In summary, our results demonstrate that alterations in the antizyme/AZI balance cause numerical centrosomal defects and suggest a role for ubiquitin-independent proteasomal degradation in centrosome duplication.

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Polyamines and cancer: old molecules, new understanding

Cited by 1,007 publications

References 104 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

Antizyme1 mediates AURKAIP1-dependent degradation of Aurora-A

Antizyme, a mediator of ubiquitin-independent proteasomal degradation and its inhibitor localize to centrosomes and modulate centriole amplification

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