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

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Abstract
β-Hydroxyisovalerylshikonin (β-HIVS), which was isolated from the plant, Lithospermum radix, induces apoptosis in various lines of human tumor cells. To identify genes involved in β-HIVS-induced apoptotic process, we performed cDNA array analysis and found that β-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 β-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 β-HIVS and this compound did not suppress the kinase activity of PLK1 in these cells. However, simultaneous treatment of K562 cells with both β-HIVS and STI571, which selectively inhibits the protein tyrosine kinase (PTK) activity of Bcr–Abl, strongly induced apoptosis. Moreover, β-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 β-HIVS-induced fragmentation of DNA. These results suggest that suppression of the activity of PLK1 via inhibition of tyrosine kinase activity by β-HIVS might play a critical role in the induction of apoptosis.

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