Transcriptional inhibition of the estrogen response element by antiestrogenic piperidinediones correlates with intercalation into DNA measured by energy calculations

Sidell, Neil; Tanmahasamut, Prasong; Ewing, Douglas E.; Hendry, Lawrence B.

doi:10.1016/j.jsbmb.2005.04.040

Cited by 11 publications

(7 citation statements)

References 48 publications

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“…Unlike most known antiestrogens, 4-CPA does not seem to bind to ER and compete with estrogen for interaction with its receptor [13]. Our recent studies have illustrated that PA and other piperidinedione derivatives can directly bind to canonical ERE motifs through intercalation into 5′-dTdG-3′: 5′-dCdA-3′ sites and that the energetic fit of the compounds is correlated with their potency to inhibit ERE reporter gene activity and proliferation of breast cancer cells [14]. Especially potent derivatives included those that formed two stereospecific hydrogen bonds with phosphate groups on adjacent DNA strands of the ERE complex.…”

Section: Discussionmentioning

confidence: 95%

“…Furthermore, this class of drugs provides a new avenue of antagonizing the estrogenic pathway without binding to the estrogen receptor [13]. In our recent studies, we have shown that PA and its derivative 4-chlorophenylacetate (4-CPA) inhibited growth of ER positive breast cancer cells but had little effect on ER negative cells, suggesting an anti-estrogenic mechanism of action [10,14]. In support of this contention, PA and 4-CPA reduced the promoter activity of the estrogen-responsive gene cyclin D1 and diminished ER activation of consensus ERE-reporter constructs.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of estrogen-induced mammary tumor formation in MMTV-aromatase transgenic mice by 4-chlorophenylacetate

et al. 2007

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Treatment of estrogen-sensitive breast cancer with selective estrogen selective modulators (SERMs) and, more recently, aromatase inhibitors has met with wide success. However, antagonism of estrogen receptor (ER) activity in breast carcinomas by SERMs such as tamoxifen has been associated with increased risk of cancer in other tissue such as the endometrium. Furthermore, current therapies using aromatase inhibitors have side effects on bone resulting in development of osteoporosis in some patients. We present in this paper the results of a study using 4-chlorophenylacetate (4-CPA), a compound which belongs to a family of small aromatic fatty acids that has been shown to possess anticancer properties, to treat DMBA exposed MMTV-aromatase mice. These animals exhibit elevated levels of estrogen in their mammary glands and develop estrogen-responsive tumors. Consistent with our earlier findings showing that 4-CPA inhibited the growth of ER positive breast cancer cells in vitro, we now demonstrate that this compound inhibits tumor formation in MMTVaromatase mice. This effect was not associated with reduction of ER expression in their mammary tissue, or to alteration of aromatase levels or activity. The data suggest that 4-CPA is a novel therapeutic agent that could be used in the prevention or treatment of estrogen-sensitive breast cancer.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Inhibition of estrogen-induced mammary tumor formation in MMTV-aromatase transgenic mice by 4-chlorophenylacetate

et al. 2007

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“…4-Substituted-aryl-1,2,3-thiadiazoles (R = H/OH) reacted with 3-aminopiperidine-2,6-dione under standard conditions to give the desired thioamides in 79% ( 3es ) and 64% ( 3et ) yields, which are transcriptional antiestrogen S -analogues. 19 4-Thiophene-1,2,3-thiadiazole reacted with n-propylamine to give the corresponding thioamide 3eu in 88% yield on a 4 mmol scale. It was further reduced to secondary amine 3ev , which was the key motif of rotigotine.…”

Section: Resultsmentioning

confidence: 99%

Thioamide synthesis via copper-catalyzed C–H activation of 1,2,3-thiadiazoles enabled by slow release and capture of thioketenes

Chang

et al. 2022

Org. Chem. Front.

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“…Utilizing transgenic mice which exhibit chronically elevated levels of estrogen in their mammary glands, these latter studies showed that 4-CPA inhibited the development and growth of estrogen-driven breast tumors. This antiestrogenic activity may be due to the ability of PA and 4-CPA to interfere with estrogen signaling through their direct binding to estrogen response element regulatory sites in the promoters of target genes [13].…”

Section: Introductionmentioning

confidence: 99%

Carcinogenic Effects in a Phenylketonuria Mouse Model

et al. 2009

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Phenylketonuria (PKU) is a metabolic disorder caused by impaired phenylalanine hydroxylase (PAH). This condition results in hyperphenylalaninemia and elevated levels of abnormal phenylalanine metabolites, among which is phenylacetic acid/phenylacetate (PA). In recent years, PA and its analogs were found to have anticancer activity against a variety of malignancies suggesting the possibility that PKU may offer protection against cancer through chronically elevated levels of PA. We tested this hypothesis in a genetic mouse model of PKU (PAHenu2) which has a biochemical profile that closely resembles that of human PKU. Plasma levels of phenylalanine in homozygous (HMZ) PAHenu2 mice were >12-fold those of heterozygous (HTZ) littermates while tyrosine levels were reduced. Phenylketones, including PA, were also markedly elevated to the range seen in the human disease. Mice were subjected to 7,12 dimethylbenz[a]anthracene (DMBA) carcinogenesis, a model which is sensitive to the anticancer effects of the PA derivative 4-chlorophenylacetate (4-CPA). Tumor induction by DMBA was not significantly different between the HTZ and HMZ mice, either in total tumor development or in the type of cancers that arose. HMZ mice were then treated with 4-CPA as positive controls for the anticancer effects of PA and to evaluate its possible effects on phenylalanine metabolism in PKU mice. 4-CPA had no effect on the plasma concentrations of phenylalanine, phenylketones, or tyrosine. Surprisingly, the HMZ mice treated with 4-CPA developed an unexplained neuromuscular syndrome which precluded its use in these animals as an anticancer agent. Together, these studies support the use of PAHenu2 mice as a model for studying human PKU. Chronically elevated levels of PA in the PAHenu2 mice were not protective against cancer.

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Transcriptional inhibition of the estrogen response element by antiestrogenic piperidinediones correlates with intercalation into DNA measured by energy calculations

Cited by 11 publications

References 48 publications

Inhibition of estrogen-induced mammary tumor formation in MMTV-aromatase transgenic mice by 4-chlorophenylacetate

Inhibition of estrogen-induced mammary tumor formation in MMTV-aromatase transgenic mice by 4-chlorophenylacetate

Thioamide synthesis via copper-catalyzed C–H activation of 1,2,3-thiadiazoles enabled by slow release and capture of thioketenes

Carcinogenic Effects in a Phenylketonuria Mouse Model

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