beta-hydroxyisovalerylshikonin inhibits the cell growth of various cancer cell lines and induces apoptosis in leukemia HL-60 cells through a mechanism different from those of Fas and etoposide

• Published in: Journal of biochemistry (Tokyo) Vol. 125; no. 1; pp. 17 - 23
• Main Authors: Hashimoto, S, Xu, M, Masuda, Y, Aiuchi, T, Nakajo, S, Cao, J, Miyakoshi, M, Ida, Y, Nakaya, K
• Format: Journal Article
• Language: English
• Published: England 01.01.1999
• Subjects: Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Calcium-Calmodulin-Dependent Protein Kinases - drug effects; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Caspase 3; Caspases - drug effects; Caspases - metabolism; Cell Division - drug effects; DNA Fragmentation - drug effects; Drug Screening Assays, Antitumor; Enzyme Activation - drug effects; Etoposide - metabolism; Etoposide - pharmacology; fas Receptor - metabolism; HL-60 Cells - drug effects; HL-60 Cells - metabolism; HL-60 Cells - pathology; Humans; Naphthoquinones - pharmacology; Nucleic Acid Synthesis Inhibitors - metabolism; Nucleic Acid Synthesis Inhibitors - pharmacology; Signal Transduction; Tumor Cells, Cultured - drug effects
• ISSN: 0021-924X
• DOI: 10.1093/oxfordjournals.jbchem.a022255

beta-Hydroxyisovalerylshikonin (beta-HIVS), which was isolated from the plant, Lithospermium radix, inhibited the growth of various lines of cancer cells derived from human solid tumors at low concentrations between 10(-8) and 10(-6) M. When HL-60 cells were treated with 10(-6) M beta-HIVS for 3 h, characteristic features of apoptosis, such as DNA fragmentation, nuclear fragmentation, and activation of caspase-3-like activity, were observed. The most characteristic features of the effect of beta-HIVS were the remarkable morphological changes induced upon treatment of HL-60 cells with beta-HIVS, as visualized on the staining of actin filaments with phalloidin labeled with tetramethylrhodamine B isothiocyanate. Moreover, activation of MAP kinases, such as ERK2, JNK and p38, was detected after treatment with 10(-6) M beta-HIVS preceding the appearance of the characteristics of apoptosis, and the features of the activation of these MAP kinases were quite different from those of Fas and anticancer drug-induced apoptosis. The activation of JNK by beta-HIVS was not inhibited by inhibitors of caspases, suggesting that JNK is located either upstream or independent of the caspase signaling pathway. beta-HIVS did not inhibit the activity of topoisomerase II. These results indicate that beta-HIVS induces apoptosis in HL-60 cells through a mechanism unlike those reported for anti-Fas antibodies and etoposide.