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

Oncogene. 2003 Feb 20;22(7):1012-23. doi: 10.1038/sj.onc.1206200.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • HL-60 Cells / enzymology
  • Humans
  • Imatinib Mesylate
  • K562 Cells / drug effects
  • K562 Cells / enzymology
  • Kidney
  • Leukemia, Myeloid / enzymology
  • Leukemia, Myeloid / pathology*
  • Naphthoquinones / pharmacology*
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology
  • Oligodeoxyribonucleotides, Antisense / pharmacology
  • Oligonucleotide Array Sequence Analysis
  • Phosphorylation / drug effects
  • Piperazines / pharmacology
  • Polo-Like Kinase 1
  • Protein Kinase Inhibitors*
  • Protein Kinases / genetics
  • Protein Kinases / 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
  • U937 Cells / enzymology

Substances

  • 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