Beta-hydroxyisovalerylshikonin induces apoptosis in human leukemia cells by inhibiting the activity of a polo-like kinase 1 (PLK1).

Abstract	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.
Authors	Yutaka Masuda, Ayano Nishida, Kouichi Hori, Takahiro Hirabayashi, Sachiko Kajimoto, Shigeo Nakajo, Takeshi Kondo, Masahiro Asaka, Kazuyasu Nakaya
Journal	Oncogene (Oncogene) Vol. 22 Issue 7 Pg. 1012-23 (Feb 20 2003) ISSN: 0950-9232 [Print] England
PMID	12592388 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antineoplastic Agents, Phytogenic Benzamides Cell Cycle Proteins Cysteine Proteinase Inhibitors DNA, Complementary Enzyme Inhibitors Naphthoquinones Neoplasm Proteins Oligodeoxyribonucleotides, Antisense Piperazines Protein Kinase Inhibitors Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 Pyrimidines beta-hydroxyisovalerylshikonin Imatinib Mesylate Genistein Protein Kinases Fusion Proteins, bcr-abl Protein Serine-Threonine Kinases polo-like kinase 1
Topics	Antineoplastic Agents, Phytogenic (pharmacology) Apoptosis (drug effects) Benzamides Cell Cycle Proteins Cell Line (drug effects) Cysteine Proteinase Inhibitors (pharmacology) DNA, Complementary (genetics) Enzyme Inhibitors (pharmacology) Fusion Proteins, bcr-abl (antagonists & inhibitors) Gene Expression Profiling Gene Expression Regulation, Leukemic (drug effects) Genistein (pharmacology) HL-60 Cells (drug effects, enzymology) Humans Imatinib Mesylate K562 Cells (drug effects, enzymology) Kidney Leukemia, Myeloid (enzymology, pathology) Naphthoquinones (pharmacology) Neoplasm Proteins (antagonists & inhibitors, genetics, physiology) Oligodeoxyribonucleotides, Antisense (pharmacology) Oligonucleotide Array Sequence Analysis Phosphorylation (drug effects) Piperazines (pharmacology) Protein Kinase Inhibitors Protein Kinases (genetics, physiology) Protein Processing, Post-Translational (drug effects) Protein Serine-Threonine Kinases Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 (physiology) Pyrimidines (pharmacology) U937 Cells (drug effects, enzymology)

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