β‐Hydroxyisovalerylshikonin Is a Novel and Potent Inhibitor of Protein Tyrosine Kinases
β‐Hydroxyisovalerylshikonin (β‐HIVS), a compound isolated from Lithospermium radix, most efficiently induced cell‐death in two lines of lung cancer cells, namely, NCI‐H522 and DMS114, whereas shikonin was effective against a wide variety of tumor cell lines. During our studies of the mechanism of ac...
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| Veröffentlicht in: | Cancer science 2002-08, Vol.93 (8), p.944-951 |
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| container_title | Cancer science |
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| creator | Hashimoto, Sachiko Xu, Ying Masuda, Yutaka Aiuchi, Toshihiro Nakajo, Shigeo Uehara, Yoshimasa Shibuya, Masabumi Yamori, Takao Nakaya, Kazuyasu |
| description | β‐Hydroxyisovalerylshikonin (β‐HIVS), a compound isolated from Lithospermium radix, most efficiently induced cell‐death in two lines of lung cancer cells, namely, NCI‐H522 and DMS114, whereas shikonin was effective against a wide variety of tumor cell lines. During our studies of the mechanism of action of β‐HIVS on tumor cells, we found that this compound inhibited protein tyrosine kinase (PTK) activity. The tyrosine kinase activities of a receptor for EGF (EGFR) and v‐Src were strongly inhibited and that of KDR/Flk–1 was weakly inhibited by β‐HIVS. The inhibition by β‐HIVS of the activities of EGFR and v‐Src was much stronger than that by shikonin. The IC50values of β‐HIVS for EGFR and v‐Src were approximately 0.7 μM and 1 μM, respectively. Moreover, the inhibition of v‐Src by β‐HIVS was non‐competitive with respect to ATP. These results strongly suggest that the action of β‐HIVS, as well as that of shikonin, involves the inhibition of PTK, and they also suggest the possibility of producing a novel group of PTK inhibitors based on shikonin as the parent compound. |
| doi_str_mv | 10.1111/j.1349-7006.2002.tb01341.x |
| format | Article |
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During our studies of the mechanism of action of β‐HIVS on tumor cells, we found that this compound inhibited protein tyrosine kinase (PTK) activity. The tyrosine kinase activities of a receptor for EGF (EGFR) and v‐Src were strongly inhibited and that of KDR/Flk–1 was weakly inhibited by β‐HIVS. The inhibition by β‐HIVS of the activities of EGFR and v‐Src was much stronger than that by shikonin. The IC50values of β‐HIVS for EGFR and v‐Src were approximately 0.7 μM and 1 μM, respectively. Moreover, the inhibition of v‐Src by β‐HIVS was non‐competitive with respect to ATP. These results strongly suggest that the action of β‐HIVS, as well as that of shikonin, involves the inhibition of PTK, and they also suggest the possibility of producing a novel group of PTK inhibitors based on shikonin as the parent compound.</description><identifier>ISSN: 0910-5050</identifier><identifier>ISSN: 1347-9032</identifier><identifier>EISSN: 1349-7006</identifier><identifier>EISSN: 1876-4673</identifier><identifier>DOI: 10.1111/j.1349-7006.2002.tb01341.x</identifier><identifier>PMID: 12716473</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>3T3 Cells ; Adenosine Triphosphate - metabolism ; Adenosine Triphosphate - pharmacology ; Animals ; Antineoplastic Agents, Phytogenic - pharmacology ; Cell Death ; Dose-Response Relationship, Drug ; EGFR ; Enzyme Inhibitors - pharmacology ; Epidermal growth factor receptors ; ErbB Receptors - metabolism ; Humans ; Inhibitory Concentration 50 ; Kinetics ; Lung cancer ; Mice ; Models, Chemical ; Naphthoquinones - pharmacology ; Protein-tyrosine kinase ; Protein-Tyrosine Kinases - antagonists & inhibitors ; Shikonin ; Src protein ; Tumor cell lines ; Tumor cells ; Tumor Cells, Cultured ; Tyrosine kinase inhibitor ; v‐Src ; β‐Hydroxyisovalerylshikonin</subject><ispartof>Cancer science, 2002-08, Vol.93 (8), p.944-951</ispartof><rights>Copyright John Wiley & Sons, Inc. 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During our studies of the mechanism of action of β‐HIVS on tumor cells, we found that this compound inhibited protein tyrosine kinase (PTK) activity. The tyrosine kinase activities of a receptor for EGF (EGFR) and v‐Src were strongly inhibited and that of KDR/Flk–1 was weakly inhibited by β‐HIVS. The inhibition by β‐HIVS of the activities of EGFR and v‐Src was much stronger than that by shikonin. The IC50values of β‐HIVS for EGFR and v‐Src were approximately 0.7 μM and 1 μM, respectively. Moreover, the inhibition of v‐Src by β‐HIVS was non‐competitive with respect to ATP. These results strongly suggest that the action of β‐HIVS, as well as that of shikonin, involves the inhibition of PTK, and they also suggest the possibility of producing a novel group of PTK inhibitors based on shikonin as the parent compound.</description><subject>3T3 Cells</subject><subject>Adenosine Triphosphate - metabolism</subject><subject>Adenosine Triphosphate - pharmacology</subject><subject>Animals</subject><subject>Antineoplastic Agents, Phytogenic - pharmacology</subject><subject>Cell Death</subject><subject>Dose-Response Relationship, Drug</subject><subject>EGFR</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Epidermal growth factor receptors</subject><subject>ErbB Receptors - metabolism</subject><subject>Humans</subject><subject>Inhibitory Concentration 50</subject><subject>Kinetics</subject><subject>Lung cancer</subject><subject>Mice</subject><subject>Models, Chemical</subject><subject>Naphthoquinones - pharmacology</subject><subject>Protein-tyrosine kinase</subject><subject>Protein-Tyrosine Kinases - antagonists & inhibitors</subject><subject>Shikonin</subject><subject>Src protein</subject><subject>Tumor cell lines</subject><subject>Tumor cells</subject><subject>Tumor Cells, Cultured</subject><subject>Tyrosine kinase inhibitor</subject><subject>v‐Src</subject><subject>β‐Hydroxyisovalerylshikonin</subject><issn>0910-5050</issn><issn>1347-9032</issn><issn>1349-7006</issn><issn>1876-4673</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqVUctOxCAUJUaj4-MXDNF1K1AoxYWJmfiYaNSFbtwQ2qEOYwWFzjjd-Ql-ix_iR_glMnHiYymQ3OQ-DueeA8AORimOZ2-c4oyKhCOUpwQhkrYlihmczpZA77u0DHpIYJQwxNAaWA9hjBDmKCerYA0TjnPKsx64fX_7eHk97YbezToT3FQ12ndNGJl7Z42FgwAVvHBT3UBlh_DKtdq2cGBHpjSt89DV8MrHZGy97rwLxmp4ZqwKOmyClVo1QW8t4ga4OT667p8m55cng_7heVJRgWhS5QVX9ZATIgTX8SnCFMFlxXXOCM0I1xUpKsQVzXhBC0IrXJSsYKquGStItgEOvnAfJ-WDHlaRoFeNfPTmQflOOmXk34o1I3nnppKJKANmEWB3AeDd00SHVo7dxNvIWRIaRYtXiNi1_9VVxTWD1_X3DxjJuS9yLOfiy7n4cu6LXPgiZ3F4-zfHn9GFET9LPJtGd_-Alv3DI0Fp9gnry5_x</recordid><startdate>200208</startdate><enddate>200208</enddate><creator>Hashimoto, Sachiko</creator><creator>Xu, Ying</creator><creator>Masuda, Yutaka</creator><creator>Aiuchi, Toshihiro</creator><creator>Nakajo, Shigeo</creator><creator>Uehara, Yoshimasa</creator><creator>Shibuya, Masabumi</creator><creator>Yamori, Takao</creator><creator>Nakaya, Kazuyasu</creator><general>Blackwell Publishing Ltd</general><general>John Wiley & Sons, Inc</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>8FE</scope><scope>8FH</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope></search><sort><creationdate>200208</creationdate><title>β‐Hydroxyisovalerylshikonin Is a Novel and Potent Inhibitor of Protein Tyrosine Kinases</title><author>Hashimoto, Sachiko ; 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During our studies of the mechanism of action of β‐HIVS on tumor cells, we found that this compound inhibited protein tyrosine kinase (PTK) activity. The tyrosine kinase activities of a receptor for EGF (EGFR) and v‐Src were strongly inhibited and that of KDR/Flk–1 was weakly inhibited by β‐HIVS. The inhibition by β‐HIVS of the activities of EGFR and v‐Src was much stronger than that by shikonin. The IC50values of β‐HIVS for EGFR and v‐Src were approximately 0.7 μM and 1 μM, respectively. Moreover, the inhibition of v‐Src by β‐HIVS was non‐competitive with respect to ATP. These results strongly suggest that the action of β‐HIVS, as well as that of shikonin, involves the inhibition of PTK, and they also suggest the possibility of producing a novel group of PTK inhibitors based on shikonin as the parent compound.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>12716473</pmid><doi>10.1111/j.1349-7006.2002.tb01341.x</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 3T3 Cells Adenosine Triphosphate - metabolism Adenosine Triphosphate - pharmacology Animals Antineoplastic Agents, Phytogenic - pharmacology Cell Death Dose-Response Relationship, Drug EGFR Enzyme Inhibitors - pharmacology Epidermal growth factor receptors ErbB Receptors - metabolism Humans Inhibitory Concentration 50 Kinetics Lung cancer Mice Models, Chemical Naphthoquinones - pharmacology Protein-tyrosine kinase Protein-Tyrosine Kinases - antagonists & inhibitors Shikonin Src protein Tumor cell lines Tumor cells Tumor Cells, Cultured Tyrosine kinase inhibitor v‐Src β‐Hydroxyisovalerylshikonin |
| title | β‐Hydroxyisovalerylshikonin Is a Novel and Potent Inhibitor of Protein Tyrosine Kinases |
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