INHIBITION OF STEROID SULFATASE ACTIVITY BY STEROIDAL METHYLTHIOPHOSPHONATES - POTENTIAL THERAPEUTIC AGENTS IN BREAST-CANCER

A PUROHIT, N M HOWARTH, B V L POTTER, M J REED

Research output: Contribution to journalArticle

Abstract

The hydrolysis of steroid sulphates, by steroid sulphatase, is an important source of oestrogenic steroids (oestrone, oestradiol and 5-androstene-3 beta,17 beta-diol) which are found in tumours. In the present study, we have examined the effect of dehydroepiandrosterone-3-O-methylthiophosphonate (DHA-3-MTP), pregnenolone-3-O-methylthiophosphonate (pregnenolone-3-MTP) and cholesterol-3-O-methylthiophosphonate (cholesterol-3-MTP) on the inhibition of oestrone sulphatase as well as DHA sulphatase activities in intact MCF-7 breast cancer cells and in placental microsomes. All three methylthiophosphonates significantly (P < 0.01) inhibited the hydrolysis of oestrone sulphate (E(1)S) in intact MCF-7 cells (31-85% inhibition at 1 mu M and 53-97% inhibition at 10 mu M). Significant inhibition of DHA sulphatase was also achieved. At a concentration of 50 mu M, all three compounds inhibited the hydrolysis of dehydroepiandrosterone sulphate (DHAS) by > 95%. Using human placental microsomes, the K-m and V-max of E(1)S were determined to be 8.1 mu M and 43 nmol/h/mg protein. The corresponding K-i values for DHA-3-MTP, pregnenolone-3-MTP and cholesterol-3-MTP were found to be 4.5, 1.4 and 6.2 mu M, respectively. Such inhibitors which are resistant to metabolism may have considerable potential as therapeutic agents and may have additional advantage over aromatase inhibitors in also reducing tumour concentrations of the oestrogenic steroid, 5-androstene-3 beta,17 beta-diol, by inhibiting the hydrolysis of DHAS.

Original languageEnglish
Pages (from-to)523-527
Number of pages5
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume48
Issue number5-6
Publication statusPublished - Apr 1994

Cite this

@article{8e3468b23f8048f7b6d0cf42bbb46de3,
title = "INHIBITION OF STEROID SULFATASE ACTIVITY BY STEROIDAL METHYLTHIOPHOSPHONATES - POTENTIAL THERAPEUTIC AGENTS IN BREAST-CANCER",
abstract = "The hydrolysis of steroid sulphates, by steroid sulphatase, is an important source of oestrogenic steroids (oestrone, oestradiol and 5-androstene-3 beta,17 beta-diol) which are found in tumours. In the present study, we have examined the effect of dehydroepiandrosterone-3-O-methylthiophosphonate (DHA-3-MTP), pregnenolone-3-O-methylthiophosphonate (pregnenolone-3-MTP) and cholesterol-3-O-methylthiophosphonate (cholesterol-3-MTP) on the inhibition of oestrone sulphatase as well as DHA sulphatase activities in intact MCF-7 breast cancer cells and in placental microsomes. All three methylthiophosphonates significantly (P < 0.01) inhibited the hydrolysis of oestrone sulphate (E(1)S) in intact MCF-7 cells (31-85{\%} inhibition at 1 mu M and 53-97{\%} inhibition at 10 mu M). Significant inhibition of DHA sulphatase was also achieved. At a concentration of 50 mu M, all three compounds inhibited the hydrolysis of dehydroepiandrosterone sulphate (DHAS) by > 95{\%}. Using human placental microsomes, the K-m and V-max of E(1)S were determined to be 8.1 mu M and 43 nmol/h/mg protein. The corresponding K-i values for DHA-3-MTP, pregnenolone-3-MTP and cholesterol-3-MTP were found to be 4.5, 1.4 and 6.2 mu M, respectively. Such inhibitors which are resistant to metabolism may have considerable potential as therapeutic agents and may have additional advantage over aromatase inhibitors in also reducing tumour concentrations of the oestrogenic steroid, 5-androstene-3 beta,17 beta-diol, by inhibiting the hydrolysis of DHAS.",
author = "A PUROHIT and HOWARTH, {N M} and POTTER, {B V L} and REED, {M J}",
year = "1994",
month = "4",
language = "English",
volume = "48",
pages = "523--527",
journal = "Journal of Steroid Biochemistry and Molecular Biology",
issn = "0960-0760",
publisher = "Elsevier Limited",
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}

INHIBITION OF STEROID SULFATASE ACTIVITY BY STEROIDAL METHYLTHIOPHOSPHONATES - POTENTIAL THERAPEUTIC AGENTS IN BREAST-CANCER. / PUROHIT, A ; HOWARTH, N M ; POTTER, B V L ; REED, M J .

In: Journal of Steroid Biochemistry and Molecular Biology, Vol. 48, No. 5-6, 04.1994, p. 523-527.

Research output: Contribution to journalArticle

TY - JOUR

T1 - INHIBITION OF STEROID SULFATASE ACTIVITY BY STEROIDAL METHYLTHIOPHOSPHONATES - POTENTIAL THERAPEUTIC AGENTS IN BREAST-CANCER

AU - PUROHIT, A

AU - HOWARTH, N M

AU - POTTER, B V L

AU - REED, M J

PY - 1994/4

Y1 - 1994/4

N2 - The hydrolysis of steroid sulphates, by steroid sulphatase, is an important source of oestrogenic steroids (oestrone, oestradiol and 5-androstene-3 beta,17 beta-diol) which are found in tumours. In the present study, we have examined the effect of dehydroepiandrosterone-3-O-methylthiophosphonate (DHA-3-MTP), pregnenolone-3-O-methylthiophosphonate (pregnenolone-3-MTP) and cholesterol-3-O-methylthiophosphonate (cholesterol-3-MTP) on the inhibition of oestrone sulphatase as well as DHA sulphatase activities in intact MCF-7 breast cancer cells and in placental microsomes. All three methylthiophosphonates significantly (P < 0.01) inhibited the hydrolysis of oestrone sulphate (E(1)S) in intact MCF-7 cells (31-85% inhibition at 1 mu M and 53-97% inhibition at 10 mu M). Significant inhibition of DHA sulphatase was also achieved. At a concentration of 50 mu M, all three compounds inhibited the hydrolysis of dehydroepiandrosterone sulphate (DHAS) by > 95%. Using human placental microsomes, the K-m and V-max of E(1)S were determined to be 8.1 mu M and 43 nmol/h/mg protein. The corresponding K-i values for DHA-3-MTP, pregnenolone-3-MTP and cholesterol-3-MTP were found to be 4.5, 1.4 and 6.2 mu M, respectively. Such inhibitors which are resistant to metabolism may have considerable potential as therapeutic agents and may have additional advantage over aromatase inhibitors in also reducing tumour concentrations of the oestrogenic steroid, 5-androstene-3 beta,17 beta-diol, by inhibiting the hydrolysis of DHAS.

AB - The hydrolysis of steroid sulphates, by steroid sulphatase, is an important source of oestrogenic steroids (oestrone, oestradiol and 5-androstene-3 beta,17 beta-diol) which are found in tumours. In the present study, we have examined the effect of dehydroepiandrosterone-3-O-methylthiophosphonate (DHA-3-MTP), pregnenolone-3-O-methylthiophosphonate (pregnenolone-3-MTP) and cholesterol-3-O-methylthiophosphonate (cholesterol-3-MTP) on the inhibition of oestrone sulphatase as well as DHA sulphatase activities in intact MCF-7 breast cancer cells and in placental microsomes. All three methylthiophosphonates significantly (P < 0.01) inhibited the hydrolysis of oestrone sulphate (E(1)S) in intact MCF-7 cells (31-85% inhibition at 1 mu M and 53-97% inhibition at 10 mu M). Significant inhibition of DHA sulphatase was also achieved. At a concentration of 50 mu M, all three compounds inhibited the hydrolysis of dehydroepiandrosterone sulphate (DHAS) by > 95%. Using human placental microsomes, the K-m and V-max of E(1)S were determined to be 8.1 mu M and 43 nmol/h/mg protein. The corresponding K-i values for DHA-3-MTP, pregnenolone-3-MTP and cholesterol-3-MTP were found to be 4.5, 1.4 and 6.2 mu M, respectively. Such inhibitors which are resistant to metabolism may have considerable potential as therapeutic agents and may have additional advantage over aromatase inhibitors in also reducing tumour concentrations of the oestrogenic steroid, 5-androstene-3 beta,17 beta-diol, by inhibiting the hydrolysis of DHAS.

M3 - Article

VL - 48

SP - 523

EP - 527

JO - Journal of Steroid Biochemistry and Molecular Biology

JF - Journal of Steroid Biochemistry and Molecular Biology

SN - 0960-0760

IS - 5-6

ER -