β-Hydroxyisovalerylshikonin has a profound anti-growth activity in human endometrial and ovarian cancer cells

Abstract

Objectives β-Hydroxyisovalerylshikonin (β-HIVS), a compound isolated from the traditional oriental medicinal herb Lithospermum radix, is an ATP non-competitive inhibitor of protein-tyrosine kinases, such as v-Src and EGFR, and it induces apoptosis in some lines of human tumor cells. We investigated the effect of β-HIVS on three endometrial cancer cell lines, two ovarian cancer cell lines, and normal human endometrial epithelial cells. Methods Endometrial and ovarian cancer cells were treated with various concentrations of β-HIVS, and its effect on cell growth, cell cycle, apoptosis, and related measurements was investigated. Results The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that all endometrial and ovarian cancer cell lines were sensitive to the growth-inhibitory effect of β-HIVS, although normal endometrial epithelial cells were viable after treatment with the same doses of β-HIVS that induced growth inhibition in endometrial and ovarian cancer cells. Cell-cycle analysis indicated that their exposure to β-HIVS decreased the proportion of cells in the S phase and increased the proportion in the G0/G1 phases of the cell cycle. Induction of apoptosis was confirmed by annexin V staining of externalized phosphatidylserine and loss of the transmembrane potential of mitochondria. This induction occurred in concert with altered expression of genes related to cell growth, malignant phenotype, and apoptosis. Conclusions These results suggest that the anticancer activity of β-HIVS may occur with higher sensitivity of cancer cells compared with normal healthy cells, when using low concentration, rising hopes that β-HIVS may become a useful adjuvant therapy for endometrial and ovarian cancers.