Isoangustone A, A Novel Licorice Compound, Inhibits Cell Proliferation by Targeting PI3K, MKK4, and MKK7 in Human Melanoma
Licorice root is known to possess various bioactivities, including anti-inflammatory and anticancer effects. Glycyrrhizin, a triterpene compound, is the most abundant constituent of dried licorice root. However, high intake or long-term consumption of glycyrrhizin causes several side effects, such a...
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| Veröffentlicht in: | Cancer prevention research (Philadelphia, Pa.) Pa.), 2013-12, Vol.6 (12), p.1293-1303 |
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| creator | NU RY SONG EUNJUNG LEE ZIGANG DONG BYUN, Sanguine KIM, Jong-Eun MOTTAMAL, Madhusoodanan JUNG HAN YOON PARK SOON SUNG LIM BODE, Ann M HYONG JOO LEE KI WON LEE |
| description | Licorice root is known to possess various bioactivities, including anti-inflammatory and anticancer effects. Glycyrrhizin, a triterpene compound, is the most abundant constituent of dried licorice root. However, high intake or long-term consumption of glycyrrhizin causes several side effects, such as hypertension, hypertensive encephalopathy, and hypokalemia. Therefore, finding additional active compounds other than glycyrrhizin in licorice that exhibit anticancer effects is worthwhile. We found that isoangustone A (IAA), a novel flavonoid from licorice root, suppressed proliferation of human melanoma cells. IAA significantly blocked cell-cycle progression at the G1-phase and inhibited the expression of G1-phase regulatory proteins, including cyclins D1 and E in the SK-MEL-28 human melanoma cell line. IAA suppressed the phosphorylation of Akt, GSK-3β, and JNK1/2. IAA also bound to phosphoinositide 3-kinase (PI3K), MKK4, and MKK7, strongly inhibiting their kinase activities in an ATP-competitive manner. Moreover, in a xenograft mouse model, IAA significantly decreased tumor growth, volume, and weight of SK-MEL-28 xenografts. Collectively, these results suggest that PI3K, MKK4, and MKK7 are the primary molecular targets of IAA in the suppression of cell proliferation. This insight into the biologic actions of IAA provides a molecular basis for the potential development of a new chemotherapeutic agent. |
| doi_str_mv | 10.1158/1940-6207.capr-13-0134 |
| format | Article |
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Glycyrrhizin, a triterpene compound, is the most abundant constituent of dried licorice root. However, high intake or long-term consumption of glycyrrhizin causes several side effects, such as hypertension, hypertensive encephalopathy, and hypokalemia. Therefore, finding additional active compounds other than glycyrrhizin in licorice that exhibit anticancer effects is worthwhile. We found that isoangustone A (IAA), a novel flavonoid from licorice root, suppressed proliferation of human melanoma cells. IAA significantly blocked cell-cycle progression at the G1-phase and inhibited the expression of G1-phase regulatory proteins, including cyclins D1 and E in the SK-MEL-28 human melanoma cell line. IAA suppressed the phosphorylation of Akt, GSK-3β, and JNK1/2. IAA also bound to phosphoinositide 3-kinase (PI3K), MKK4, and MKK7, strongly inhibiting their kinase activities in an ATP-competitive manner. Moreover, in a xenograft mouse model, IAA significantly decreased tumor growth, volume, and weight of SK-MEL-28 xenografts. Collectively, these results suggest that PI3K, MKK4, and MKK7 are the primary molecular targets of IAA in the suppression of cell proliferation. This insight into the biologic actions of IAA provides a molecular basis for the potential development of a new chemotherapeutic agent.</description><identifier>ISSN: 1940-6207</identifier><identifier>EISSN: 1940-6215</identifier><identifier>DOI: 10.1158/1940-6207.capr-13-0134</identifier><identifier>PMID: 24104352</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Animals ; Anti-Inflammatory Agents - pharmacology ; Apoptosis - drug effects ; Biological and medical sciences ; Blotting, Western ; Cell Adhesion - drug effects ; Cell Cycle - drug effects ; Cell Proliferation - drug effects ; Dermatology ; Flow Cytometry ; Glycyrrhiza - chemistry ; Glycyrrhizic Acid - pharmacology ; Humans ; Immunoprecipitation ; Isoflavones - pharmacology ; Male ; MAP Kinase Kinase 4 - antagonists & inhibitors ; MAP Kinase Kinase 4 - metabolism ; MAP Kinase Kinase 7 - antagonists & inhibitors ; MAP Kinase Kinase 7 - metabolism ; Medical sciences ; Melanoma - drug therapy ; Melanoma - metabolism ; Melanoma - pathology ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Miscellaneous ; Models, Molecular ; Phosphatidylinositol 3-Kinases - antagonists & inhibitors ; Phosphatidylinositol 3-Kinases - metabolism ; Phosphorylation - drug effects ; Prevention and actions ; Public health. Hygiene ; Public health. Hygiene-occupational medicine ; Tumor Cells, Cultured ; Tumors of the skin and soft tissue. Premalignant lesions ; Xenograft Model Antitumor Assays</subject><ispartof>Cancer prevention research (Philadelphia, Pa.), 2013-12, Vol.6 (12), p.1293-1303</ispartof><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c455t-3eb874988530c5e0dd81325c996425fc65221a499e05449fe0653d419f1517283</citedby><cites>FETCH-LOGICAL-c455t-3eb874988530c5e0dd81325c996425fc65221a499e05449fe0653d419f1517283</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3343,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=28040191$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24104352$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>NU RY SONG</creatorcontrib><creatorcontrib>EUNJUNG LEE</creatorcontrib><creatorcontrib>ZIGANG DONG</creatorcontrib><creatorcontrib>BYUN, Sanguine</creatorcontrib><creatorcontrib>KIM, Jong-Eun</creatorcontrib><creatorcontrib>MOTTAMAL, Madhusoodanan</creatorcontrib><creatorcontrib>JUNG HAN YOON PARK</creatorcontrib><creatorcontrib>SOON SUNG LIM</creatorcontrib><creatorcontrib>BODE, Ann M</creatorcontrib><creatorcontrib>HYONG JOO LEE</creatorcontrib><creatorcontrib>KI WON LEE</creatorcontrib><title>Isoangustone A, A Novel Licorice Compound, Inhibits Cell Proliferation by Targeting PI3K, MKK4, and MKK7 in Human Melanoma</title><title>Cancer prevention research (Philadelphia, Pa.)</title><addtitle>Cancer Prev Res (Phila)</addtitle><description>Licorice root is known to possess various bioactivities, including anti-inflammatory and anticancer effects. Glycyrrhizin, a triterpene compound, is the most abundant constituent of dried licorice root. However, high intake or long-term consumption of glycyrrhizin causes several side effects, such as hypertension, hypertensive encephalopathy, and hypokalemia. Therefore, finding additional active compounds other than glycyrrhizin in licorice that exhibit anticancer effects is worthwhile. We found that isoangustone A (IAA), a novel flavonoid from licorice root, suppressed proliferation of human melanoma cells. IAA significantly blocked cell-cycle progression at the G1-phase and inhibited the expression of G1-phase regulatory proteins, including cyclins D1 and E in the SK-MEL-28 human melanoma cell line. IAA suppressed the phosphorylation of Akt, GSK-3β, and JNK1/2. IAA also bound to phosphoinositide 3-kinase (PI3K), MKK4, and MKK7, strongly inhibiting their kinase activities in an ATP-competitive manner. Moreover, in a xenograft mouse model, IAA significantly decreased tumor growth, volume, and weight of SK-MEL-28 xenografts. Collectively, these results suggest that PI3K, MKK4, and MKK7 are the primary molecular targets of IAA in the suppression of cell proliferation. This insight into the biologic actions of IAA provides a molecular basis for the potential development of a new chemotherapeutic agent.</description><subject>Animals</subject><subject>Anti-Inflammatory Agents - pharmacology</subject><subject>Apoptosis - drug effects</subject><subject>Biological and medical sciences</subject><subject>Blotting, Western</subject><subject>Cell Adhesion - drug effects</subject><subject>Cell Cycle - drug effects</subject><subject>Cell Proliferation - drug effects</subject><subject>Dermatology</subject><subject>Flow Cytometry</subject><subject>Glycyrrhiza - chemistry</subject><subject>Glycyrrhizic Acid - pharmacology</subject><subject>Humans</subject><subject>Immunoprecipitation</subject><subject>Isoflavones - pharmacology</subject><subject>Male</subject><subject>MAP Kinase Kinase 4 - antagonists & inhibitors</subject><subject>MAP Kinase Kinase 4 - metabolism</subject><subject>MAP Kinase Kinase 7 - antagonists & inhibitors</subject><subject>MAP Kinase Kinase 7 - metabolism</subject><subject>Medical sciences</subject><subject>Melanoma - drug therapy</subject><subject>Melanoma - metabolism</subject><subject>Melanoma - pathology</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>Miscellaneous</subject><subject>Models, Molecular</subject><subject>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phosphorylation - drug effects</subject><subject>Prevention and actions</subject><subject>Public health. Hygiene</subject><subject>Public health. Hygiene-occupational medicine</subject><subject>Tumor Cells, Cultured</subject><subject>Tumors of the skin and soft tissue. Premalignant lesions</subject><subject>Xenograft Model Antitumor Assays</subject><issn>1940-6207</issn><issn>1940-6215</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkE1PGzEQhi1UxPdfQL5U6iELHn_s2sdoRSFKaCMEZ8vxeoPRrp3au5Xg15MoKT3NK80zM5oHoWsgNwBC3oLipCgpqW6s2aQCWEGA8SN0dmiA-PaVSXWKznN-I6SkkrITdEo5EM4EPUMfsxxNWI95iMHh6QRP8a_413V44W1M3jpcx34Tx9BM8Cy8-pUfMq5d1-Flip1vXTKDjwGv3vGzSWs3-LDGyxmbT_DjfM4n2IRmlyrsA34YexPwo-tMiL25RMet6bK7OtQL9PLz7rl-KBa_72f1dFFYLsRQMLeSFVdSCkascKRpJDAqrFIlp6K1paAUDFfKEcG5ah0pBWs4qBYEVFSyC_Rjv3eT4p_R5UH3PtvtCya4OGYNvBRya4zxLVruUZtizsm1epN8b9K7BqJ33vVOqd4p1fV0-aSBabIfvD7cGFe9a77G_oneAt8PgMnWdG0ywfr8n5OEE1DAPgE3LogU</recordid><startdate>20131201</startdate><enddate>20131201</enddate><creator>NU RY SONG</creator><creator>EUNJUNG LEE</creator><creator>ZIGANG DONG</creator><creator>BYUN, Sanguine</creator><creator>KIM, Jong-Eun</creator><creator>MOTTAMAL, Madhusoodanan</creator><creator>JUNG HAN YOON PARK</creator><creator>SOON SUNG LIM</creator><creator>BODE, Ann M</creator><creator>HYONG JOO LEE</creator><creator>KI WON LEE</creator><general>American Association for Cancer Research</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>20131201</creationdate><title>Isoangustone A, A Novel Licorice Compound, Inhibits Cell Proliferation by Targeting PI3K, MKK4, and MKK7 in Human Melanoma</title><author>NU RY SONG ; EUNJUNG LEE ; ZIGANG DONG ; BYUN, Sanguine ; KIM, Jong-Eun ; MOTTAMAL, Madhusoodanan ; JUNG HAN YOON PARK ; SOON SUNG LIM ; BODE, Ann M ; HYONG JOO LEE ; KI WON LEE</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c455t-3eb874988530c5e0dd81325c996425fc65221a499e05449fe0653d419f1517283</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Anti-Inflammatory Agents - pharmacology</topic><topic>Apoptosis - drug effects</topic><topic>Biological and medical sciences</topic><topic>Blotting, Western</topic><topic>Cell Adhesion - drug effects</topic><topic>Cell Cycle - drug effects</topic><topic>Cell Proliferation - drug effects</topic><topic>Dermatology</topic><topic>Flow Cytometry</topic><topic>Glycyrrhiza - chemistry</topic><topic>Glycyrrhizic Acid - pharmacology</topic><topic>Humans</topic><topic>Immunoprecipitation</topic><topic>Isoflavones - pharmacology</topic><topic>Male</topic><topic>MAP Kinase Kinase 4 - antagonists & inhibitors</topic><topic>MAP Kinase Kinase 4 - metabolism</topic><topic>MAP Kinase Kinase 7 - antagonists & inhibitors</topic><topic>MAP Kinase Kinase 7 - metabolism</topic><topic>Medical sciences</topic><topic>Melanoma - drug therapy</topic><topic>Melanoma - metabolism</topic><topic>Melanoma - pathology</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Nude</topic><topic>Miscellaneous</topic><topic>Models, Molecular</topic><topic>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Phosphorylation - drug effects</topic><topic>Prevention and actions</topic><topic>Public health. Hygiene</topic><topic>Public health. Hygiene-occupational medicine</topic><topic>Tumor Cells, Cultured</topic><topic>Tumors of the skin and soft tissue. Premalignant lesions</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>NU RY SONG</creatorcontrib><creatorcontrib>EUNJUNG LEE</creatorcontrib><creatorcontrib>ZIGANG DONG</creatorcontrib><creatorcontrib>BYUN, Sanguine</creatorcontrib><creatorcontrib>KIM, Jong-Eun</creatorcontrib><creatorcontrib>MOTTAMAL, Madhusoodanan</creatorcontrib><creatorcontrib>JUNG HAN YOON PARK</creatorcontrib><creatorcontrib>SOON SUNG LIM</creatorcontrib><creatorcontrib>BODE, Ann M</creatorcontrib><creatorcontrib>HYONG JOO LEE</creatorcontrib><creatorcontrib>KI WON LEE</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>Cancer prevention research (Philadelphia, Pa.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>NU RY SONG</au><au>EUNJUNG LEE</au><au>ZIGANG DONG</au><au>BYUN, Sanguine</au><au>KIM, Jong-Eun</au><au>MOTTAMAL, Madhusoodanan</au><au>JUNG HAN YOON PARK</au><au>SOON SUNG LIM</au><au>BODE, Ann M</au><au>HYONG JOO LEE</au><au>KI WON LEE</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Isoangustone A, A Novel Licorice Compound, Inhibits Cell Proliferation by Targeting PI3K, MKK4, and MKK7 in Human Melanoma</atitle><jtitle>Cancer prevention research (Philadelphia, Pa.)</jtitle><addtitle>Cancer Prev Res (Phila)</addtitle><date>2013-12-01</date><risdate>2013</risdate><volume>6</volume><issue>12</issue><spage>1293</spage><epage>1303</epage><pages>1293-1303</pages><issn>1940-6207</issn><eissn>1940-6215</eissn><abstract>Licorice root is known to possess various bioactivities, including anti-inflammatory and anticancer effects. Glycyrrhizin, a triterpene compound, is the most abundant constituent of dried licorice root. However, high intake or long-term consumption of glycyrrhizin causes several side effects, such as hypertension, hypertensive encephalopathy, and hypokalemia. Therefore, finding additional active compounds other than glycyrrhizin in licorice that exhibit anticancer effects is worthwhile. We found that isoangustone A (IAA), a novel flavonoid from licorice root, suppressed proliferation of human melanoma cells. IAA significantly blocked cell-cycle progression at the G1-phase and inhibited the expression of G1-phase regulatory proteins, including cyclins D1 and E in the SK-MEL-28 human melanoma cell line. IAA suppressed the phosphorylation of Akt, GSK-3β, and JNK1/2. IAA also bound to phosphoinositide 3-kinase (PI3K), MKK4, and MKK7, strongly inhibiting their kinase activities in an ATP-competitive manner. Moreover, in a xenograft mouse model, IAA significantly decreased tumor growth, volume, and weight of SK-MEL-28 xenografts. Collectively, these results suggest that PI3K, MKK4, and MKK7 are the primary molecular targets of IAA in the suppression of cell proliferation. This insight into the biologic actions of IAA provides a molecular basis for the potential development of a new chemotherapeutic agent.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>24104352</pmid><doi>10.1158/1940-6207.capr-13-0134</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Cancer prevention research (Philadelphia, Pa.), 2013-12, Vol.6 (12), p.1293-1303 |
| issn | 1940-6207 1940-6215 |
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| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals |
| subjects | Animals Anti-Inflammatory Agents - pharmacology Apoptosis - drug effects Biological and medical sciences Blotting, Western Cell Adhesion - drug effects Cell Cycle - drug effects Cell Proliferation - drug effects Dermatology Flow Cytometry Glycyrrhiza - chemistry Glycyrrhizic Acid - pharmacology Humans Immunoprecipitation Isoflavones - pharmacology Male MAP Kinase Kinase 4 - antagonists & inhibitors MAP Kinase Kinase 4 - metabolism MAP Kinase Kinase 7 - antagonists & inhibitors MAP Kinase Kinase 7 - metabolism Medical sciences Melanoma - drug therapy Melanoma - metabolism Melanoma - pathology Mice Mice, Inbred BALB C Mice, Nude Miscellaneous Models, Molecular Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphatidylinositol 3-Kinases - metabolism Phosphorylation - drug effects Prevention and actions Public health. Hygiene Public health. Hygiene-occupational medicine Tumor Cells, Cultured Tumors of the skin and soft tissue. Premalignant lesions Xenograft Model Antitumor Assays |
| title | Isoangustone A, A Novel Licorice Compound, Inhibits Cell Proliferation by Targeting PI3K, MKK4, and MKK7 in Human Melanoma |
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