title: Beta-hydroxyisovalerylshikonin is a novel and potent inhibitor of protein tyrosine kinases.
abstract: Beta-hydroxyisovalerylshikonin (beta-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 beta-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 beta-HIVS. The inhibition by beta-HIVS of the activities of EGFR and v-Src was much stronger than that by shikonin. The IC50 values of beta-HIVS for EGFR and v-Src were approximately 0.7 microM and 1 microM, respectively. Moreover, the inhibition of v-Src by beta-HIVS was non-competitive with respect to ATP. These results strongly suggest that the action of beta-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.
authors.affiliation: The Laboratory of Biological Chemistry, School of Pharmaceutical Sciences, Showa University, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Hashimoto
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Masuda
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Aiuchi
authors.forename: Shigeo
authors.initials: S
authors.lastname: Nakajo
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Uehara
authors.forename: Masabumi
authors.initials: M
authors.lastname: Shibuya
authors.forename: Takao
authors.initials: T
authors.lastname: Yamori
authors.forename: Kazuyasu
authors.initials: K
authors.lastname: Nakaya
mesh_terms: D016475:3T3 Cells; D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D016923:Cell Death; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D051379:Mice; D008956:Models, Chemical; D009285:Naphthoquinones / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D009285:Naphthoquinones; C118460:beta-hydroxyisovalerylshikonin; C016101:shikonin; D000255:Adenosine Triphosphate; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases