An estrogen-dependent esterase activity in MCF-7 cells

Katz, Joseph; Finlay, Thomas H.; Banerjee, Sila; Levitz, Mortimer

doi:10.1016/0022-4731(87)91040-5

Cited by 31 publications

(14 citation statements)

References 20 publications

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“…More work is obviously needed on the enzyme in mammary cancer cells. In agreement with the studies of Katz et al [61], the activity of the esterase towards E2-1713 oleate as substrate was unaffected by growing MCF-7 cells in the presence of E 2 [58].…”

Section: Lipoidal Estrogen Esterase (Enzyme 5supporting

confidence: 87%

“…Thus, no direct evidence that the esterase in human breast cancer cells was under polypeptide hormonal control via c-AMP could be obtained. Despite this, the enzyme in these cells was very sensitive to diisopropyl ftuorophosphate [58,61], and it is too early to dismiss the possibility of a hormone-induced activation via phosphorylation. More work is obviously needed on the enzyme in mammary cancer cells.…”

Section: Lipoidal Estrogen Esterase (Enzyme 5mentioning

confidence: 91%

“…Fig. 1) Katz et al [61] reported the presence of an esterase (s) in homogenates of MCF-7 cells which could hydrolyse E2-1713 esters such as E2-1713 acetate, E2-17 ~ valerate, and E2-1713 stearate. The esterase responsible for hydrolysing E2-1713 acetate was evidently different from that which hydrolysed the latter two esters since, at saturating concentrations, they failed to inhibit hydrolysis of the acetate.…”

Section: Fattyacyl Coa: Estradiol-1713 Acyi Transferase (Enzyme 4 Fimentioning

confidence: 94%

“…The esterase responsible for hydrolysing E2-1713 acetate was evidently different from that which hydrolysed the latter two esters since, at saturating concentrations, they failed to inhibit hydrolysis of the acetate. Furthermore, activity towards E2-17 ~ acetate was exclusively stimulated by addition of E 2 to MCF-7 cultures [61].…”

Section: Fattyacyl Coa: Estradiol-1713 Acyi Transferase (Enzyme 4 Fimentioning

confidence: 99%

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Enzymatic regulation of estradiol-17β concentrations in human breast cancer cells

Adams¹

1991

Breast Cancer Res Tr

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Estradiol-17 beta is known to be involved in both the etiology and maintenance of growth of breast cancer. However, blood levels of the hormone do not reflect those found within the cells due to a number of transformations catalysed by enzymes which may be under metabolite and/or hormonal regulation. Recognition of the importance of the hormone microenvironment within the cell focuses attention on these enzymes and provides the subject for this review. An interplay between the sex hormones, estrogen and progestin, can control estradiol-17 beta concentrations in breast cancer cells at the level of key transforming enzymes. In addition, some enzymes catalyse production of biologically inert derivatives which are rapidly eliminated from the cell. Other enzymes catalyse the formation of derivatives which are exclusively intracellular and can act as reserve forms of the hormone. Yet others lead to estradiol-17 beta metabolites which are cytotoxic. An improved understanding of the enzymes and the role of the related metabolites can provide the opportunity for the development of new therapeutic agents.

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Section: Lipoidal Estrogen Esterase (Enzyme 5supporting

confidence: 87%

Section: Lipoidal Estrogen Esterase (Enzyme 5mentioning

confidence: 91%

Section: Fattyacyl Coa: Estradiol-1713 Acyi Transferase (Enzyme 4 Fimentioning

confidence: 94%

Section: Fattyacyl Coa: Estradiol-1713 Acyi Transferase (Enzyme 4 Fimentioning

confidence: 99%

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Enzymatic regulation of estradiol-17β concentrations in human breast cancer cells

Adams¹

1991

Breast Cancer Res Tr

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“…On these cells, only compound 5 showed a antiproliferative effect, which is of comparable magnitude to that shown by the reference compound ferrocenyl diphenol 2 (IC 50 (5) = 0.5 lM; IC 50 (2) = 0.6 lM). This strongly suggests that enzymes in the living cells hydrolysed the ester function of 5 to generate the dihydroxyl derivative 2 in situ, as observed in other systems such as ester-estrogen cleavage [41][42][43] and the activation of fluorescent probes [44]. Compound 2 can then engage in QM formation to give rise to cytotoxic effects.…”

Section: Effect Of the Compounds On The Growth Of Breast Cancer Cellsmentioning

confidence: 98%

Ferrocenyl compounds possessing protected phenol and thiophenol groups: Synthesis, X-ray structure, and in vitro biological effects against breast cancer

Heilmann

Hillard

Plamont

et al. 2008

Journal of Organometallic Chemistry

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We have previously shown that conjugated ferrocenyl p-phenols show strong cytotoxic effects against both the hormone-dependent MCF-7 and hormone-independent MDA-MB-231 breast cancer cell lines, possibly via metabolic quinone methide (QM) formation. To further evaluate this proposed mechanism, we have created a series of ferrocenyl prodrugs containing methyl and acetyl-protected thio-and oxo-phenols: 2-ferrocenyl-1,1-bis(4-acetoxyphenyl)-but-1-ene (5), 2-ferrocenyl-1,1-bis(4-thioacetylphenyl)-but-1-ene (6), 2-ferrocenyl-1,1-bis(4-methoxyphenyl)-but-1-ene (7), and 2-ferrocenyl-1,1-bis(4-thiomethylphenyl)-but-1-ene (8), which might be activated by hydrolysis enzymes in situ. Only the acetoxy 5 displayed antiproliferative effects (IC 50 on MDA-MB-231 of 0.5 lM) while 6-8 act as pure estrogens (proliferative on MCF-7 and little to no effect on MDA-MB-231). The behaviour of 5 is similar to that previously found for the free phenol 2-ferrocenyl-1,1-di(4-hydroxyphenyl)-but-1-ene (2), indicating that 5 is metabolized in situ to 2, which could then undergo oxidative QM formation. The observation that the thioacetyl 6 is not cytotoxic suggests that the in situ oxidative chemistry of the putative ferrocenyl thiophenol is different from that of 2. Because p-thioquinone methides are practically unknown, the negative results for 6 further implicate the bioformation of the QM in the case of 2 and related compounds. The lack of cytotoxicity of 7 and 8 can be attributed to lack of efficient hydrolysis in situ. Estrogen receptor binding affinity studies for the compounds and the X-ray structure of 8 are also reported.

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Synthesis of novel flexible tamoxifen analogues to overcome CYP2D6 polymorphism and their biological evaluation on MCF‐7 cell line

Ahmed

Wober

2020

Drug Development Research

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Tamoxifen (TAM) is currently the endocrine treatment of choice for all stages of breast cancer; it has proven success in ER positive and ER negative patients. TAM is activated by endogenous CYP450 enzymes to the more biologically active metabolites 4-hydroxytamoxifen and endoxifen mainly via CYP2D6 and CYP3A4/5. CYP2D6 has been investigated for polymorphism; there is a large interindividual variation in the enzyme activity, this drastically effects clinical outcomes of tamoxifen treatment. Here in we report the design and synthesis of 10 novel compounds bearing a modified tamoxifen skeleton, ring C is substituted with different ester groups to bypass the CYP2D6 enzyme metabolism and employ esterase enzymes for activation. All compounds endorse flexibility on ring A. Compounds (II-X) showed MCF-7% growth inhibition >50% at a screening dose of 10 μM. These results were validated by yeast estrogen screen (YES) and E-Screen assay combined with XTT assay. Compound II (E/Z 4-[1-4-(3-Dimethylaminopropoxy)-phenyl)-3-(4-methoxy-phenyl)-2-methyl-propenyl]-phenol) showed nanomolar antiestrogenic activity (IC 50 = 510 nM in YES assay) and was five times more potent in inhibiting the growth of MCF-7 BUS (IC 50 = 96 nM) compared to TAM (IC 50 = 503 nM).Esterified analogues VI, VII were three times more active than TAM on MCF-7 BUS (IC 50 = 167 nM). Novel analogues are prodrugs that can ensure equal clinical outcomes to all breast cancer patients. K E Y W O R D S

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An estrogen-dependent esterase activity in MCF-7 cells

Cited by 31 publications

References 20 publications

Enzymatic regulation of estradiol-17β concentrations in human breast cancer cells

Enzymatic regulation of estradiol-17β concentrations in human breast cancer cells

Ferrocenyl compounds possessing protected phenol and thiophenol groups: Synthesis, X-ray structure, and in vitro biological effects against breast cancer

Synthesis of novel flexible tamoxifen analogues to overcome CYP2D6 polymorphism and their biological evaluation on MCF‐7 cell line

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