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.
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.
Hashimoto
S
S
The Laboratories of Biological Chemistry Capital Normal University 105, Beijing, 100037, China.
Xu
M
M
Masuda
Y
Y
Aiuchi
T
T
Nakajo
S
S
Cao
J
J
Miyakoshi
M
M
Ida
Y
Y
Nakaya
K
K
D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D005047:Etoposide / Q000378:metabolism / Q000494:pharmacology*; D018922:HL-60 Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D009285:Naphthoquinones / Q000494:pharmacology*; D019384:Nucleic Acid Synthesis Inhibitors / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured / Q000187:drug effects; D019014:fas Receptor / Q000378:metabolism*
D000970:Antineoplastic Agents; D009285:Naphthoquinones; D019384:Nucleic Acid Synthesis Inhibitors; C118460:beta-hydroxyisovalerylshikonin; D019014:fas Receptor; C016101:shikonin; D005047:Etoposide; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases