5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, a mechanism-based inhibitor of NAD(P)H:quinone oxidoreductase 1, exhibits activity against human pancreatic cancer in vitro and in vivo
The enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) has been found to be up-regulated in pancreatic cancer as well as many other solid tumors. A recent study showed that inhibition of NQO1 in pancreatic cancer cells using the nonselective inhibitor dicumarol suppressed the malignant phenotype. The au...
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| creator | Dehn, Donna L Siegel, David Zafar, Khan Shoeb Reigan, Philip Swann, Elizabeth Moody, Christopher J Ross, David |
| description | The enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) has been found to be up-regulated in pancreatic cancer as well as many
other solid tumors. A recent study showed that inhibition of NQO1 in pancreatic cancer cells using the nonselective inhibitor
dicumarol suppressed the malignant phenotype. The authors suggested that inhibition of cell growth might result from an increase
in intracellular superoxide production due to inhibition of NQO1. We have recently shown that NQO1 can directly scavenge superoxide
and this effect may become physiologically relevant in cells containing high NQO1 levels. We therefore tested the hypothesis
that 5-methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione (ES936), a specific mechanism-based inhibitor of NQO1,
would be an effective agent for the treatment of pancreatic tumors. The human pancreatic tumor cell lines BxPC-3 and MIA PaCa-2
contain high levels of NQO1 activity and protein as verified by immunoblot and immunocytochemical staining of human pancreatic
tumor cells. ES936 treatment inhibited NQO1 activity by >98% in MIA PaCa-2 and BxPC-3 cells. In addition, ES936 treatment
induced growth inhibition [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay] in MIA PaCa-2 and BxPC-3 cells
with an IC 50 of 108 and 365 nmol/L, respectively. Treatment of MIA PaCa-2 cells with ES936 also inhibited the ability of these cells to
form colonies and grow in soft agar in a dose-dependent manner. Treatment of mice carrying MIA PaCa-2 xenograft tumors with
ES936 resulted in a significant difference in growth rates in ES936-treated and DMSO-treated (control) tumors. Our data did
not show an increase in either intracellular superoxide production or oxygen consumption after treatment of cells with ES936,
contrary to the effects seen with dicumarol. In summary, mechanism-based inhibitors of NQO1, such as ES936, may be useful
therapeutic agents for the treatment of pancreatic cancer, although the underlying mechanism seems to be independent of superoxide
generation. [Mol Cancer Ther 2006;5(7):1702–9] |
| doi_str_mv | 10.1158/1535-7163.MCT-06-0105 |
| format | Article |
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other solid tumors. A recent study showed that inhibition of NQO1 in pancreatic cancer cells using the nonselective inhibitor
dicumarol suppressed the malignant phenotype. The authors suggested that inhibition of cell growth might result from an increase
in intracellular superoxide production due to inhibition of NQO1. We have recently shown that NQO1 can directly scavenge superoxide
and this effect may become physiologically relevant in cells containing high NQO1 levels. We therefore tested the hypothesis
that 5-methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione (ES936), a specific mechanism-based inhibitor of NQO1,
would be an effective agent for the treatment of pancreatic tumors. The human pancreatic tumor cell lines BxPC-3 and MIA PaCa-2
contain high levels of NQO1 activity and protein as verified by immunoblot and immunocytochemical staining of human pancreatic
tumor cells. ES936 treatment inhibited NQO1 activity by >98% in MIA PaCa-2 and BxPC-3 cells. In addition, ES936 treatment
induced growth inhibition [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay] in MIA PaCa-2 and BxPC-3 cells
with an IC 50 of 108 and 365 nmol/L, respectively. Treatment of MIA PaCa-2 cells with ES936 also inhibited the ability of these cells to
form colonies and grow in soft agar in a dose-dependent manner. Treatment of mice carrying MIA PaCa-2 xenograft tumors with
ES936 resulted in a significant difference in growth rates in ES936-treated and DMSO-treated (control) tumors. Our data did
not show an increase in either intracellular superoxide production or oxygen consumption after treatment of cells with ES936,
contrary to the effects seen with dicumarol. In summary, mechanism-based inhibitors of NQO1, such as ES936, may be useful
therapeutic agents for the treatment of pancreatic cancer, although the underlying mechanism seems to be independent of superoxide
generation. [Mol Cancer Ther 2006;5(7):1702–9]</description><identifier>ISSN: 1535-7163</identifier><identifier>EISSN: 1538-8514</identifier><identifier>DOI: 10.1158/1535-7163.MCT-06-0105</identifier><identifier>PMID: 16891456</identifier><language>eng</language><publisher>United States: American Association for Cancer Research</publisher><subject>Animals ; Antineoplastic Agents - pharmacology ; Cell Proliferation - drug effects ; Cell Respiration - drug effects ; dicumarol ; diphtheria toxin diaphorase ; Enzyme Inhibitors - pharmacology ; Female ; Humans ; Indolequinones - pharmacology ; mechanism-based inhibitor ; Mice ; Mice, Nude ; NAD(P)H Dehydrogenase (Quinone) - analysis ; NAD(P)H Dehydrogenase (Quinone) - antagonists & inhibitors ; NQO1 ; Oxygen Consumption - drug effects ; pancreatic cancer ; Pancreatic Neoplasms - enzymology ; quinone ; superoxide ; Superoxides - analysis ; Superoxides - metabolism ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays</subject><ispartof>Molecular cancer therapeutics, 2006-07, Vol.5 (7), p.1702-1709</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c339t-ab6856ce2ad8f930ca8b11f265a30a5652f44d0f7f97cebb93f7c50d0086aa4f3</citedby><cites>FETCH-LOGICAL-c339t-ab6856ce2ad8f930ca8b11f265a30a5652f44d0f7f97cebb93f7c50d0086aa4f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3342,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16891456$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dehn, Donna L</creatorcontrib><creatorcontrib>Siegel, David</creatorcontrib><creatorcontrib>Zafar, Khan Shoeb</creatorcontrib><creatorcontrib>Reigan, Philip</creatorcontrib><creatorcontrib>Swann, Elizabeth</creatorcontrib><creatorcontrib>Moody, Christopher J</creatorcontrib><creatorcontrib>Ross, David</creatorcontrib><title>5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, a mechanism-based inhibitor of NAD(P)H:quinone oxidoreductase 1, exhibits activity against human pancreatic cancer in vitro and in vivo</title><title>Molecular cancer therapeutics</title><addtitle>Mol Cancer Ther</addtitle><description>The enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) has been found to be up-regulated in pancreatic cancer as well as many
other solid tumors. A recent study showed that inhibition of NQO1 in pancreatic cancer cells using the nonselective inhibitor
dicumarol suppressed the malignant phenotype. The authors suggested that inhibition of cell growth might result from an increase
in intracellular superoxide production due to inhibition of NQO1. We have recently shown that NQO1 can directly scavenge superoxide
and this effect may become physiologically relevant in cells containing high NQO1 levels. We therefore tested the hypothesis
that 5-methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione (ES936), a specific mechanism-based inhibitor of NQO1,
would be an effective agent for the treatment of pancreatic tumors. The human pancreatic tumor cell lines BxPC-3 and MIA PaCa-2
contain high levels of NQO1 activity and protein as verified by immunoblot and immunocytochemical staining of human pancreatic
tumor cells. ES936 treatment inhibited NQO1 activity by >98% in MIA PaCa-2 and BxPC-3 cells. In addition, ES936 treatment
induced growth inhibition [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay] in MIA PaCa-2 and BxPC-3 cells
with an IC 50 of 108 and 365 nmol/L, respectively. Treatment of MIA PaCa-2 cells with ES936 also inhibited the ability of these cells to
form colonies and grow in soft agar in a dose-dependent manner. Treatment of mice carrying MIA PaCa-2 xenograft tumors with
ES936 resulted in a significant difference in growth rates in ES936-treated and DMSO-treated (control) tumors. Our data did
not show an increase in either intracellular superoxide production or oxygen consumption after treatment of cells with ES936,
contrary to the effects seen with dicumarol. In summary, mechanism-based inhibitors of NQO1, such as ES936, may be useful
therapeutic agents for the treatment of pancreatic cancer, although the underlying mechanism seems to be independent of superoxide
generation. [Mol Cancer Ther 2006;5(7):1702–9]</description><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Respiration - drug effects</subject><subject>dicumarol</subject><subject>diphtheria toxin diaphorase</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Female</subject><subject>Humans</subject><subject>Indolequinones - pharmacology</subject><subject>mechanism-based inhibitor</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>NAD(P)H Dehydrogenase (Quinone) - analysis</subject><subject>NAD(P)H Dehydrogenase (Quinone) - antagonists & inhibitors</subject><subject>NQO1</subject><subject>Oxygen Consumption - drug effects</subject><subject>pancreatic cancer</subject><subject>Pancreatic Neoplasms - enzymology</subject><subject>quinone</subject><subject>superoxide</subject><subject>Superoxides - analysis</subject><subject>Superoxides - metabolism</subject><subject>Tumor Cells, Cultured</subject><subject>Xenograft Model Antitumor Assays</subject><issn>1535-7163</issn><issn>1538-8514</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkcFu1DAQQCMEoqXwCSCfoJXWxU5iJ-mtWgpFaoFDOSFkTZxJY5TYWztZdn-Rr6rTrMTJM543M5Zfkrzl7JxzUX7kIhO04DI7v13fUSYp40w8S47jfUlLwfPnT_HCHCWvQvjDGC-rlL9MjrgsK54LeZz8E_QWx87t9pSvUtqYIWb7nmb012lOrRm923RoY_1sqfw2tnE90nxVRNpZXBEgA-oOrAkDrSFgQ4ztTG1G54lrybfLT6c_zq4vHiZjI0_czjTOYzPpMcKErwjunvBAQI9ma8Y9gXswNoykmwawZANWe4TRaKJjiD4uINv5bQRssyRb9zp50UIf8M3hPEl-fr66W1_Tm-9fvq4vb6jOsmqkUMtSSI0pNGVbZUxDWXPeplJAxkBIkbZ53rC2aKtCY11XWVtowRrGSgmQt9lJ8n6Zu_HuYcIwqsEEjX0PFt0UlCwLXuRpEUGxgNq7EDy2auPNAH6vOFOzRDULUrMgFSUqJtUsMfa9OyyY6gGb_10HaxH4sACdue_-Go9q-RaPAcHrTsWhihcszR4BoeCpEA</recordid><startdate>20060701</startdate><enddate>20060701</enddate><creator>Dehn, Donna L</creator><creator>Siegel, David</creator><creator>Zafar, Khan Shoeb</creator><creator>Reigan, Philip</creator><creator>Swann, Elizabeth</creator><creator>Moody, Christopher J</creator><creator>Ross, David</creator><general>American Association for Cancer Research</general><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>20060701</creationdate><title>5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, a mechanism-based inhibitor of NAD(P)H:quinone oxidoreductase 1, exhibits activity against human pancreatic cancer in vitro and in vivo</title><author>Dehn, Donna L ; Siegel, David ; Zafar, Khan Shoeb ; Reigan, Philip ; Swann, Elizabeth ; Moody, Christopher J ; Ross, David</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c339t-ab6856ce2ad8f930ca8b11f265a30a5652f44d0f7f97cebb93f7c50d0086aa4f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Cell Proliferation - drug effects</topic><topic>Cell Respiration - drug effects</topic><topic>dicumarol</topic><topic>diphtheria toxin diaphorase</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Female</topic><topic>Humans</topic><topic>Indolequinones - pharmacology</topic><topic>mechanism-based inhibitor</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>NAD(P)H Dehydrogenase (Quinone) - analysis</topic><topic>NAD(P)H Dehydrogenase (Quinone) - antagonists & inhibitors</topic><topic>NQO1</topic><topic>Oxygen Consumption - drug effects</topic><topic>pancreatic cancer</topic><topic>Pancreatic Neoplasms - enzymology</topic><topic>quinone</topic><topic>superoxide</topic><topic>Superoxides - analysis</topic><topic>Superoxides - metabolism</topic><topic>Tumor Cells, Cultured</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dehn, Donna L</creatorcontrib><creatorcontrib>Siegel, David</creatorcontrib><creatorcontrib>Zafar, Khan Shoeb</creatorcontrib><creatorcontrib>Reigan, Philip</creatorcontrib><creatorcontrib>Swann, Elizabeth</creatorcontrib><creatorcontrib>Moody, Christopher J</creatorcontrib><creatorcontrib>Ross, David</creatorcontrib><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>Molecular cancer therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dehn, Donna L</au><au>Siegel, David</au><au>Zafar, Khan Shoeb</au><au>Reigan, Philip</au><au>Swann, Elizabeth</au><au>Moody, Christopher J</au><au>Ross, David</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, a mechanism-based inhibitor of NAD(P)H:quinone oxidoreductase 1, exhibits activity against human pancreatic cancer in vitro and in vivo</atitle><jtitle>Molecular cancer therapeutics</jtitle><addtitle>Mol Cancer Ther</addtitle><date>2006-07-01</date><risdate>2006</risdate><volume>5</volume><issue>7</issue><spage>1702</spage><epage>1709</epage><pages>1702-1709</pages><issn>1535-7163</issn><eissn>1538-8514</eissn><abstract>The enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) has been found to be up-regulated in pancreatic cancer as well as many
other solid tumors. A recent study showed that inhibition of NQO1 in pancreatic cancer cells using the nonselective inhibitor
dicumarol suppressed the malignant phenotype. The authors suggested that inhibition of cell growth might result from an increase
in intracellular superoxide production due to inhibition of NQO1. We have recently shown that NQO1 can directly scavenge superoxide
and this effect may become physiologically relevant in cells containing high NQO1 levels. We therefore tested the hypothesis
that 5-methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione (ES936), a specific mechanism-based inhibitor of NQO1,
would be an effective agent for the treatment of pancreatic tumors. The human pancreatic tumor cell lines BxPC-3 and MIA PaCa-2
contain high levels of NQO1 activity and protein as verified by immunoblot and immunocytochemical staining of human pancreatic
tumor cells. ES936 treatment inhibited NQO1 activity by >98% in MIA PaCa-2 and BxPC-3 cells. In addition, ES936 treatment
induced growth inhibition [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay] in MIA PaCa-2 and BxPC-3 cells
with an IC 50 of 108 and 365 nmol/L, respectively. Treatment of MIA PaCa-2 cells with ES936 also inhibited the ability of these cells to
form colonies and grow in soft agar in a dose-dependent manner. Treatment of mice carrying MIA PaCa-2 xenograft tumors with
ES936 resulted in a significant difference in growth rates in ES936-treated and DMSO-treated (control) tumors. Our data did
not show an increase in either intracellular superoxide production or oxygen consumption after treatment of cells with ES936,
contrary to the effects seen with dicumarol. In summary, mechanism-based inhibitors of NQO1, such as ES936, may be useful
therapeutic agents for the treatment of pancreatic cancer, although the underlying mechanism seems to be independent of superoxide
generation. [Mol Cancer Ther 2006;5(7):1702–9]</abstract><cop>United States</cop><pub>American Association for Cancer Research</pub><pmid>16891456</pmid><doi>10.1158/1535-7163.MCT-06-0105</doi><tpages>8</tpages></addata></record> |
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| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals |
| subjects | Animals Antineoplastic Agents - pharmacology Cell Proliferation - drug effects Cell Respiration - drug effects dicumarol diphtheria toxin diaphorase Enzyme Inhibitors - pharmacology Female Humans Indolequinones - pharmacology mechanism-based inhibitor Mice Mice, Nude NAD(P)H Dehydrogenase (Quinone) - analysis NAD(P)H Dehydrogenase (Quinone) - antagonists & inhibitors NQO1 Oxygen Consumption - drug effects pancreatic cancer Pancreatic Neoplasms - enzymology quinone superoxide Superoxides - analysis Superoxides - metabolism Tumor Cells, Cultured Xenograft Model Antitumor Assays |
| title | 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, a mechanism-based inhibitor of NAD(P)H:quinone oxidoreductase 1, exhibits activity against human pancreatic cancer in vitro and in vivo |
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