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Mol. Hum. Reprod. Advance Access published online on January 3, 2006
Molecular Human Reproduction, doi:10.1093/molehr/gah249
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© The Author 2005. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received October 12, 2005
Revised November 21, 2005
Accepted November 22, 2005

Article

Bufalin induces apoptosis and the G0/G1 cell cycle arrest of endometriotic stromal cells: a promising agent for the treatment of endometriosis

Kaei Nasu 1 *, Masakazu Nishida 2, Tami Ueda 2, Noriyuki Takai 2, Sun Bing 2, Hisashi Narahara 2, and Isao Miyakawa 2

1 Department of Obstetrics and Gynecology, Oita University, Hasama-machi, Oita 879-5593, Japan
2 Department of Obstetrics and Gynecology, Oita University, Hasama-machi, Oita, Japan

* To whom correspondence should be addressed.
Kaei Nasu, E-mail: nasu{at}med.oita-u.ac.jp


  Abstract

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. Bufalin is a major digoxin-like immunoreactive component isolated from the skin and parotid venom glands of toad and is considered an apoptosis-inducing agent. To apply bufalin to the medical treatment of endometriosis, we investigated the effects of this agent on the cell proliferation and apoptosis of 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 bufalin on the cell cycle of ECSC was also determined by flow cytometry. The expression of apoptosis- and cell cycle-related molecules was also examined in ECSC using Western blot analysis. Bufalin significantly inhibited the cell proliferation and DNA synthesis of ECSC and induced apoptosis and the G0/G1 phase cell cycle arrest of these cells. The down-regulation of the cyclin A, Bcl-2, and Bcl-XL expression with the simultaneous up-regulation of the p21 and Bax expression, and caspase-9 activation was observed in ECSC after bufalin treatment. It is suggested that bufalin induces apoptosis of ECSC by simultaneously suppressing anti-apoptotic proteins and inducing pro-apoptotic proteins. Caspase-9-mediated cascade is involved in this mechanism. Therefore, bufalin could be used as a therapeutic agent for the treatment of endometriosis.

Keywords: apoptosis/bufalin/caspase-9/cell cycle/endometriosis.
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