Simvastatin inhibits the proliferation and the contractility of human endometriotic stromal cells: a promising agent for the treatment of endometriosis

Nasu, Kaei; Yuge, Akitoshi; Tsuno, Akitoshi; Narahara, Hisashi

doi:10.1016/j.fertnstert.2009.06.055

Cited by 41 publications

(39 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have also found that simvastatin protects against development of experimental endometriosis by human endometrial tissues using a nude mouse model [13]. Comparable beneficial effects of statins were also reported in other in vivo and in vitro systems [14][15][16][17][18]. The current study was designed to investigate whether simvastatin may affect adhesiveness and invasiveness of HES cells as well as expression of selected genes relevant to adhesiveness and invasiveness: MMP2, MMP3, TIMP2, and CD44.…”

Section: Introductionmentioning

confidence: 84%

Simvastatin Decreases Invasiveness of Human Endometrial Stromal Cells1

Sokalska

Cress

Bruner‐Tran

et al. 2012

Biology of Reproduction

View full text Add to dashboard Cite

Recently we reported that statins, the competitive inhibitors of the key enzyme regulating the mevalonate pathway, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), decrease proliferation of human endometrial stromal (HES) cells. Furthermore, we found that simvastatin treatment reduces the number and the size of endometrial implants in a nude mouse model of endometriosis. The present study was undertaken to investigate the effect of simvastatin on HES cell invasiveness and on expression of selected genes relevant to invasiveness: matrix metalloproteinase 2 (MMP2), MMP3, tissue inhibitor of matrix metalloproteinase 2 (TIMP2), and CD44. Because statin-induced inhibition of HMGCR reduces the production of substrates for isoprenylation-geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP)-the effects of GGPP and FPP were also evaluated. Simvastatin induced a concentration-dependent reduction of invasiveness of HES cells. This effect of simvastatin was abrogated by GGPP but not by FPP. Simvastatin also reduced the mRNA levels of MMP2, MMP3, and CD44, but increased TIMP2 mRNA; all these effects of simvastatin were partly or entirely reversed in the presence of GGPP. The present findings provide a novel mechanism of action of simvastatin on endometrial stroma that may explain reduction of endometriosis in animal models of this disease. Furthermore, the presently described effects of simvastatin are likely mediated, at least in part, by inhibition of geranylgeranylation.

show abstract

Section: Introductionmentioning

confidence: 84%

Simvastatin Decreases Invasiveness of Human Endometrial Stromal Cells1

Sokalska

Cress

Bruner‐Tran

et al. 2012

Biology of Reproduction

View full text Add to dashboard Cite

show abstract

“…In vitro cultures of hESCs to which simvastatin was added have displayed a statistically significant, dose-dependent reduction in the number of viable cells and cell adhesion as well as increased apoptosis (25,26). Altered cell morphology related to the F-actin cytoskeleton also was a consistent finding, which can be associated with impaired cell adhesion and motility.…”

Section: Statinsmentioning

confidence: 88%

Pharmacologic therapies in endometriosis: a systematic review

Soares¹,

Martínez-Varea

Hidalgo-Mora

et al. 2012

Fertility and Sterility

138

View full text Add to dashboard Cite

“…22 The proposed mechanisms of actions of statins on endometriosis implants are stimulation of apoptosis, inhibition of endometrial cell proliferation, blockage of angiogenesis, disruption of adherence and invasion of endometrial cells to peritoneum, and decrease in oxidative stress and inflammation. 10,[22][23][24][25][26] Decreased sensitivity of endometrial tissue to spontaneous apoptosis contributes to the implantation and growth of endometrium at ectopic sites. 27 Ectopic endometriosis implants demonstrate high ERK1/2 signaling pathway activity resulting in enhanced cell survival.…”

Section: Discussionmentioning

confidence: 99%

“…28 Statins may decrease the proliferation of endometrial stromal cells by blocking the activation of this pathway. 24,25,28 Statins may also induce apoptotic cell death by stimulating caspase 3/7 in endometrial stromal cells. 26 In order to implant and grow, refluxed endometrial cells need to establish cell-to-cell or cell-to-extracellular matrix interactions with the peritoneal lining and invade extracellular matrix after initial attachment.…”

Section: Discussionmentioning

confidence: 99%

Statins Inhibit Monocyte Chemotactic Protein 1 Expression in Endometriosis

et al. 2012

View full text Add to dashboard Cite

Statins are potent inhibitors of the endogenous mevalonate pathway. Besides inhibiting cholesterol biosynthesis, statins may also demonstrate anti-inflammatory properties. Inflammation is implicated in the attachment and invasion of endometrial cells to the peritoneal surface and growth of ectopic endometrium by inducing proliferation and angiogenesis. In this study, the effect of statins on monocyte chemotactic protein 1 (MCP-1) expression in endometriotic implants in nude mouse model and in cultured endometriotic cells was evaluated. In mouse model, simvastatin decreased MCP-1 expression in a dose-dependent manner in endometriotic implants (P < .05). Similarly, both simvastatin and mevastatin revealed a dose-dependent inhibition of MCP-1 production in cultured endometriotic cells (P < .01). This inhibitory effect of the statins on MCP-1 production was reversed by the downstream substrates of the mevalonate pathway. Moreover, statins decreased MCP-1 messenger RNA expression in cultured endometriotic cells (P < .05). In conclusion, statins exert anti-inflammatory effect in endometriotic cells and could provide a potential treatment of endometriosis in the future.

show abstract

Simvastatin inhibits the proliferation and the contractility of human endometriotic stromal cells: a promising agent for the treatment of endometriosis

Cited by 41 publications

References 22 publications

Simvastatin Decreases Invasiveness of Human Endometrial Stromal Cells1

Simvastatin Decreases Invasiveness of Human Endometrial Stromal Cells1

Pharmacologic therapies in endometriosis: a systematic review

Statins Inhibit Monocyte Chemotactic Protein 1 Expression in Endometriosis

Contact Info

Product

Resources

About