Beta-hydroxyisovalerylshikonin induces apoptosis and G0/G1 cell-cycle arrest of endometriotic stromal cells: a preliminary in vitro study.
BACKGROUND
Most of the current medical treatments for endometriosis aim to down-regulate the estrogen activity. However, a high recurrence rate after medical treatments has been the most significant problem. Beta-hydroxyisovalerylshikonin (beta-HIVS) is an ATP non-competitive inhibitor of protein-tyrosine kinases and is considered an apoptosis-inducing agent. The aim of this study is to evaluate the effects of beta-HIVS on the proliferation, cell cycle and apoptosis of endometriotic stromal cells.


METHODS
We investigated the effects of beta-HIVS on cultured ovarian endometriotic cyst stromal cells (ECSC) by a modified methylthiazoletetrazolium (MTT) assay, a 5-bromo-2'-deoxyuridine (BrdU) incorporation assay and internucleosomal DNA fragmentation assays. The effect of beta-HIVS on the cell cycle of ECSC was determined by flow cytometry. The expression of apoptosis-related molecules was examined in ECSC using western blot analysis.


RESULTS
Beta-HIVS significantly inhibited the proliferation and DNA synthesis of ECSC and induced apoptosis and G0/G1 phase cell-cycle arrest of these cells. Down-regulation of the B-cell lymphoma/leukaemia-2 (Bcl-2) expression with the activation of caspase-3, caspase-8 and caspase-9 was observed in ECSC after beta-HIVS treatment.


CONCLUSIONS
These results suggest that beta-HIVS induces apoptosis of ECSC by suppressing anti-apoptotic proteins. Although our present findings are preliminary, beta-HIVS could potentially be a therapeutic agent for the treatment of endometriosis.
Nishida
M
M
Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Oita, Japan.
Nasu
K
K
Ueda
T
T
Yuge
A
A
Takai
N
N
Narahara
H
H
D017209:Apoptosis / Q000187:drug effects*; D001973:Bromodeoxyuridine; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation; D004715:Endometriosis / Q000473:pathology*; D005260:Female; D016193:G1 Phase; D016195:G2 Phase; D006801:Humans; D066298:In Vitro Techniques; D009285:Naphthoquinones / Q000494:pharmacology*; D017697:Premenopause; D016192:Resting Phase, Cell Cycle; D016196:S Phase; D017154:Stromal Cells / Q000187:drug effects / Q000473:pathology*
D009285:Naphthoquinones; C118460:beta-hydroxyisovalerylshikonin; D001973:Bromodeoxyuridine