Beta-hydroxyisovalerylshikonin induces apoptosis in human leukemia cells by inhibiting the activity of a polo-like kinase 1 (PLK1).
beta-Hydroxyisovalerylshikonin (beta-HIVS), which was isolated from the plant, Lithospermum radix, induces apoptosis in various lines of human tumor cells. To identify genes involved in beta-HIVS-induced apoptotic process, we performed cDNA array analysis and found that beta-HIVS suppresses the expression of the gene for a polo-like kinase 1 (PLK1) that is involved in control of the cell cycle. When U937 and HL60 cells were treated with 10(-6) M beta-HIVS for 0.5 h, both the amount of PLK1 itself and the kinase activity of this enzyme were decreased. By contrast, Bcr-Abl-positive K562 cells were resistant to the induction of apoptosis by beta-HIVS and this compound did not suppress the kinase activity of PLK1 in these cells. However, simultaneous treatment of K562 cells with both beta-HIVS and STI571, which selectively inhibits the protein tyrosine kinase (PTK) activity of Bcr-Abl, strongly induced apoptosis. Moreover, beta-HIVS increased the inhibitory effect of STI571 on PTK activity. Treatment of K562 cells with antisense oligodeoxynucleotides (ODNs) specific for PLK1 sensitized these cells to the beta-HIVS-induced fragmentation of DNA. These results suggest that suppression of the activity of PLK1 via inhibition of tyrosine kinase activity by beta-HIVS might play a critical role in the induction of apoptosis.
Masuda
Yutaka
Y
Laboratory of Biological Chemistry, School of Pharmaceutical Sciences, Showa University, Tokyo 142-8555, Japan.
Nishida
Ayano
A
Hori
Kouichi
K
Hirabayashi
Takahiro
T
Kajimoto
Sachiko
S
Nakajo
Shigeo
S
Kondo
Takeshi
T
Asaka
Masahiro
M
Nakaya
Kazuyasu
K
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D018797:Cell Cycle Proteins; D002460:Cell Line / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D018076:DNA, Complementary / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology; D018922:HL-60 Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells / Q000187:drug effects / Q000201:enzymology; D007668:Kidney; D007951:Leukemia, Myeloid / Q000201:enzymology / Q000473:pathology*; D009285:Naphthoquinones / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology; D020298:U937 Cells / Q000187:drug effects / Q000201:enzymology; D000097869:Polo-Like Kinase 1
D000972:Antineoplastic Agents, Phytogenic; D001549:Benzamides; D018797:Cell Cycle Proteins; D015853:Cysteine Proteinase Inhibitors; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D016044:Fusion Proteins, bcr-abl; D019833:Genistein; D000068877:Imatinib Mesylate; D009285:Naphthoquinones; D009363:Neoplasm Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D000097869:Polo-Like Kinase 1; C118460:beta-hydroxyisovalerylshikonin