Inhibition of steroid sulphatase activity by steroidal methylthiophosphonates: Potential therapeutic agents in breast cancer
The hydrolysis of steroid sulphates, by steroid sulphatase, is an important source of oestrogenic steroids (oestrone, oestradiol and 5-androstene-3β,17β-diol) which are found in tumours. In the present study, we have examined the effect of dehydroepiandrosterone-3- O-methylthiophosphonate (DHA-3-MTP...
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| Veröffentlicht in: | The Journal of steroid biochemistry and molecular biology 1994-04, Vol.48 (5), p.523-527 |
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| container_title | The Journal of steroid biochemistry and molecular biology |
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| creator | Purohit, A. Howarth, N.M. Potter, B.V.L. Reed, M.J. |
| description | The hydrolysis of steroid sulphates, by steroid sulphatase, is an important source of oestrogenic steroids (oestrone, oestradiol and 5-androstene-3β,17β-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 μM and 53–97% inhibition at 10 μM). Significant inhibition of DHA sulphatase was also achieved. At a concentration of 50 μM, all three compounds inhibited the hydrolysis of dehydroepiandrosterone sulphate (DHAS) by > 95%. Using human placental microsomes, the
K
m
and
V
max of E
1S were determined to be 8.1 μM 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 μM, 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-3β,17β-diol, by inhibiting the hydrolysis of DHAS. |
| doi_str_mv | 10.1016/0960-0760(94)90203-8 |
| format | Article |
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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 μM and 53–97% inhibition at 10 μM). Significant inhibition of DHA sulphatase was also achieved. At a concentration of 50 μM, all three compounds inhibited the hydrolysis of dehydroepiandrosterone sulphate (DHAS) by > 95%. Using human placental microsomes, the
K
m
and
V
max of E
1S were determined to be 8.1 μM 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 μM, 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-3β,17β-diol, by inhibiting the hydrolysis of DHAS.</description><identifier>ISSN: 0960-0760</identifier><identifier>EISSN: 1879-1220</identifier><identifier>DOI: 10.1016/0960-0760(94)90203-8</identifier><identifier>PMID: 8180114</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>Antineoplastic agents ; Antineoplastic Agents - pharmacology ; Arylsulfatases - antagonists & inhibitors ; Biological and medical sciences ; Breast Neoplasms - drug therapy ; Breast Neoplasms - enzymology ; Cholesterol - analogs & derivatives ; Cholesterol - pharmacology ; Cholesterol - therapeutic use ; Dehydroepiandrosterone - analogs & derivatives ; Dehydroepiandrosterone - pharmacology ; Dehydroepiandrosterone - therapeutic use ; Dose-Response Relationship, Drug ; Female ; General aspects ; Humans ; Medical sciences ; Microsomes - enzymology ; Pharmacology. Drug treatments ; Placenta - enzymology ; Pregnancy ; Pregnenolone - analogs & derivatives ; Pregnenolone - pharmacology ; Pregnenolone - therapeutic use ; Steryl-Sulfatase ; Tumor Cells, Cultured</subject><ispartof>The Journal of steroid biochemistry and molecular biology, 1994-04, Vol.48 (5), p.523-527</ispartof><rights>1994</rights><rights>1994 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c301t-9c0089e3695f1751f4f438da8d1401885d0e81baf4aa29db2fcad942e7ac2db43</citedby><cites>FETCH-LOGICAL-c301t-9c0089e3695f1751f4f438da8d1401885d0e81baf4aa29db2fcad942e7ac2db43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/0960-0760(94)90203-8$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,778,782,3539,27907,27908,45978</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=4061149$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8180114$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Purohit, A.</creatorcontrib><creatorcontrib>Howarth, N.M.</creatorcontrib><creatorcontrib>Potter, B.V.L.</creatorcontrib><creatorcontrib>Reed, M.J.</creatorcontrib><title>Inhibition of steroid sulphatase activity by steroidal methylthiophosphonates: Potential therapeutic agents in breast cancer</title><title>The Journal of steroid biochemistry and molecular biology</title><addtitle>J Steroid Biochem Mol Biol</addtitle><description>The hydrolysis of steroid sulphates, by steroid sulphatase, is an important source of oestrogenic steroids (oestrone, oestradiol and 5-androstene-3β,17β-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 μM and 53–97% inhibition at 10 μM). Significant inhibition of DHA sulphatase was also achieved. At a concentration of 50 μM, all three compounds inhibited the hydrolysis of dehydroepiandrosterone sulphate (DHAS) by > 95%. Using human placental microsomes, the
K
m
and
V
max of E
1S were determined to be 8.1 μM 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 μM, 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-3β,17β-diol, by inhibiting the hydrolysis of DHAS.</description><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Arylsulfatases - antagonists & inhibitors</subject><subject>Biological and medical sciences</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - enzymology</subject><subject>Cholesterol - analogs & derivatives</subject><subject>Cholesterol - pharmacology</subject><subject>Cholesterol - therapeutic use</subject><subject>Dehydroepiandrosterone - analogs & derivatives</subject><subject>Dehydroepiandrosterone - pharmacology</subject><subject>Dehydroepiandrosterone - therapeutic use</subject><subject>Dose-Response Relationship, Drug</subject><subject>Female</subject><subject>General aspects</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Microsomes - enzymology</subject><subject>Pharmacology. Drug treatments</subject><subject>Placenta - enzymology</subject><subject>Pregnancy</subject><subject>Pregnenolone - analogs & derivatives</subject><subject>Pregnenolone - pharmacology</subject><subject>Pregnenolone - therapeutic use</subject><subject>Steryl-Sulfatase</subject><subject>Tumor Cells, Cultured</subject><issn>0960-0760</issn><issn>1879-1220</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1994</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMGKFDEQhoMo6-zqGyjkIKKH1kp3pjvxIMiy6sKCHvQcqpNqO9LTaZP0woAPb8YZ5-ghFOT_qpL6GHsm4I0A0b4F3UIFXQuvtHytoYamUg_YRqhOV6Ku4SHbnJHH7DKlnwDQNKK7YBdKKBBCbtjv23n0vc8-zDwMPGWKwTue1mkZMWMijjb7e5_3vN__i3HiO8rjfsqjD8sYUjkzZkrv-NeQac6-EHmkiAut2VuOP8pl4n7mfSRMmVucLcUn7NGAU6Knp3rFvn-8-Xb9ubr78un2-sNdZRsQudIWQGlqWr0dRLcVgxxkoxwqJyQIpbYOSIkeB4lYa9fXg0WnZU0d2tr1srliL49zlxh-rZSy2flkaZpwprAm07VSSah1AeURtDGkFGkwS_Q7jHsjwBykm4NRczBqtDR_pRtV2p6f5q_9jty56WS55C9OOSaL0xDL9j6dMQltoQ6vvz9iVFzce4omWU9FlPORbDYu-P__4w-BO6D1</recordid><startdate>199404</startdate><enddate>199404</enddate><creator>Purohit, A.</creator><creator>Howarth, N.M.</creator><creator>Potter, B.V.L.</creator><creator>Reed, M.J.</creator><general>Elsevier Ltd</general><general>Elsevier Science</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>199404</creationdate><title>Inhibition of steroid sulphatase activity by steroidal methylthiophosphonates: Potential therapeutic agents in breast cancer</title><author>Purohit, A. ; Howarth, N.M. ; Potter, B.V.L. ; Reed, M.J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c301t-9c0089e3695f1751f4f438da8d1401885d0e81baf4aa29db2fcad942e7ac2db43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1994</creationdate><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Arylsulfatases - antagonists & inhibitors</topic><topic>Biological and medical sciences</topic><topic>Breast Neoplasms - drug therapy</topic><topic>Breast Neoplasms - enzymology</topic><topic>Cholesterol - analogs & derivatives</topic><topic>Cholesterol - pharmacology</topic><topic>Cholesterol - therapeutic use</topic><topic>Dehydroepiandrosterone - analogs & derivatives</topic><topic>Dehydroepiandrosterone - pharmacology</topic><topic>Dehydroepiandrosterone - therapeutic use</topic><topic>Dose-Response Relationship, Drug</topic><topic>Female</topic><topic>General aspects</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Microsomes - enzymology</topic><topic>Pharmacology. Drug treatments</topic><topic>Placenta - enzymology</topic><topic>Pregnancy</topic><topic>Pregnenolone - analogs & derivatives</topic><topic>Pregnenolone - pharmacology</topic><topic>Pregnenolone - therapeutic use</topic><topic>Steryl-Sulfatase</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Purohit, A.</creatorcontrib><creatorcontrib>Howarth, N.M.</creatorcontrib><creatorcontrib>Potter, B.V.L.</creatorcontrib><creatorcontrib>Reed, M.J.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of steroid biochemistry and molecular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Purohit, A.</au><au>Howarth, N.M.</au><au>Potter, B.V.L.</au><au>Reed, M.J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of steroid sulphatase activity by steroidal methylthiophosphonates: Potential therapeutic agents in breast cancer</atitle><jtitle>The Journal of steroid biochemistry and molecular biology</jtitle><addtitle>J Steroid Biochem Mol Biol</addtitle><date>1994-04</date><risdate>1994</risdate><volume>48</volume><issue>5</issue><spage>523</spage><epage>527</epage><pages>523-527</pages><issn>0960-0760</issn><eissn>1879-1220</eissn><abstract>The hydrolysis of steroid sulphates, by steroid sulphatase, is an important source of oestrogenic steroids (oestrone, oestradiol and 5-androstene-3β,17β-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 μM and 53–97% inhibition at 10 μM). Significant inhibition of DHA sulphatase was also achieved. At a concentration of 50 μM, all three compounds inhibited the hydrolysis of dehydroepiandrosterone sulphate (DHAS) by > 95%. Using human placental microsomes, the
K
m
and
V
max of E
1S were determined to be 8.1 μM 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 μM, 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-3β,17β-diol, by inhibiting the hydrolysis of DHAS.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>8180114</pmid><doi>10.1016/0960-0760(94)90203-8</doi><tpages>5</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-0760 |
| ispartof | The Journal of steroid biochemistry and molecular biology, 1994-04, Vol.48 (5), p.523-527 |
| issn | 0960-0760 1879-1220 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_76484029 |
| source | Elsevier ScienceDirect Journals Complete - AutoHoldings; MEDLINE |
| subjects | Antineoplastic agents Antineoplastic Agents - pharmacology Arylsulfatases - antagonists & inhibitors Biological and medical sciences Breast Neoplasms - drug therapy Breast Neoplasms - enzymology Cholesterol - analogs & derivatives Cholesterol - pharmacology Cholesterol - therapeutic use Dehydroepiandrosterone - analogs & derivatives Dehydroepiandrosterone - pharmacology Dehydroepiandrosterone - therapeutic use Dose-Response Relationship, Drug Female General aspects Humans Medical sciences Microsomes - enzymology Pharmacology. Drug treatments Placenta - enzymology Pregnancy Pregnenolone - analogs & derivatives Pregnenolone - pharmacology Pregnenolone - therapeutic use Steryl-Sulfatase Tumor Cells, Cultured |
| title | Inhibition of steroid sulphatase activity by steroidal methylthiophosphonates: Potential therapeutic agents in breast cancer |
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