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: Sachiko Hashimoto, Ying Xu, Yutaka Masuda, Toshihiro Aiuchi, Shigeo Nakajo, Yoshimasa Uehara, Masabumi Shibuya, Takao Yamori, Kazuyasu Nakaya
• Journal: Japanese journal of cancer research : Gann (Jpn J Cancer Res) Vol. 93 Issue 8 Pg. 944-51 (Aug 2002) ISSN: 0910-5050 [Print] Japan
• PMID: 12716473 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Enzyme Inhibitors
• Naphthoquinones
• beta-hydroxyisovalerylshikonin
• shikonin
• Adenosine Triphosphate
• ErbB Receptors
• Protein-Tyrosine Kinases

Topics

• 3T3 Cells
• Adenosine Triphosphate (metabolism, pharmacology)
• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Cell Death
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• ErbB Receptors (metabolism)
• Humans
• Inhibitory Concentration 50
• Kinetics
• Mice
• Models, Chemical
• Naphthoquinones (pharmacology)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Tumor Cells, Cultured