Beta-hydroxyisovalerylshikonin has a profound anti-growth activity in human endometrial and ovarian cancer cells.
OBJECTIVE
Beta-hydroxyisovalerylshikonin (beta-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 beta-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 beta-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 beta-HIVS, although normal endometrial epithelial cells were viable after treatment with the same doses of beta-HIVS that induced growth inhibition in endometrial and ovarian cancer cells. Cell-cycle analysis indicated that their exposure to beta-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 beta-HIVS may occur with higher sensitivity of cancer cells compared with normal healthy cells, when using low concentration, rising hopes that beta-HIVS may become a useful adjuvant therapy for endometrial and ovarian cancers.
Takai
Noriyuki
N
Department of Obstetrics and Gynecology, Oita University Faculty of Medicine, Oita, Japan. takai@med.oita-u.ac.jp
Ueda
Tami
T
Nishida
Masakazu
M
Nasu
Kaei
K
Narahara
Hisashi
H
D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009285:Naphthoquinones / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects
C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047908:Intracellular Signaling Peptides and Proteins; D009285:Naphthoquinones; C118460:beta-hydroxyisovalerylshikonin; D050760:Cyclin-Dependent Kinase Inhibitor p27