WAY-202196, a selective estrogen receptor-beta agonist, protects against death in experimental septic shock

Cristofaro, Patricia; Opal, Steven M.; Palardy, John E.; Parejo, Nicolas A.; Jhung, Jhung; Keith, James C.; Harris, Heather A.

doi:10.1097/01.ccm.0000227173.13497.56

Cited by 59 publications

(40 citation statements)

References 33 publications

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“…It was shown to have anxiolytic and antidepressant effects, which may be useful in affective disorders (Hughes et al 2008). ERb agonist was also shown to improve survival in animal models of severe sepsis due to its protective effects on gastrointestinal barrier function (Cristofaro et al 2006). Furthermore, a selective ERb modulator, MF101, has been shown to reduce menopausal symptoms in phase 2 clinical trials (Grady et al 2009, Stovall & Pinkerton 2009).…”

Section: Discussionmentioning

confidence: 99%

Targeting estrogen receptor subtypes (ERα and ERβ) with selective ER modulators in ovarian cancer

Chan

Leung

Chan

et al. 2014

Journal of Endocrinology

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Ovarian cancer cells express both estrogen receptor a (ERa) and ERb, and hormonal therapy is an attractive treatment option because of its relatively few side effects. However, estrogen was previously shown to have opposite effects in tumors expressing ERa compared with ERb, indicating that the two receptor subtypes may have opposing effects. This may explain the modest response to nonselective estrogen inhibition in clinical practice. In this study, we aimed to investigate the effect of selectively targeting each ER subtype on ovarian cancer growth. Ovarian cancer cell lines SKOV3 and OV2008, expressing both ER subtypes, were treated with highly selective ER modulators. These results were confirmed on a xenograft model where SKOV3 cells were injected s.c. into ovariectomized mice. We observed that the average size of xenografts in both the DPN-treated group and the MPP-treated group was significantly smaller than that for the vehicle-treated group. In addition, we found that phospho-AKT expressions in SKOV3 cells were reduced by 80% after treatment with MPP and DPN, indicating that the AKT pathway was involved. The combined treatment with MPP and DPN had a synergistic effect in suppressing ovarian cancer cell growth. Our findings indicate that targeting ER subtypes may enhance the response to hormonal treatment in women with ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

Targeting estrogen receptor subtypes (ERα and ERβ) with selective ER modulators in ovarian cancer

Chan

Leung

Chan

et al. 2014

Journal of Endocrinology

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mentioning

confidence: 99%

“…For example, ER-␣ decreases proinflammatory cytokine production by splenic macrophages and Kupffer cells after traumahemorrhage (33, 34). On the other hand, ER-␤ decreases inflammatory markers and mortality in shock-induced lung injury (5,42).In this context, the recently discovered nongenomic effects of estrogen have gained much attention (21). In contrast to the well-described genomic effects, which occur at a transcriptional level and which take hours to days to develop, nongenomic mechanisms use existing proteins and signaling pathways, therefore taking only seconds to minutes to mediate their effects.…”

mentioning

confidence: 99%

Selective estrogen receptor-α and estrogen receptor-β agonists rapidly decrease pulmonary artery vasoconstriction by a nitric oxide-dependent mechanism

Lahm¹,

Crisostomo²,

Markel³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Selective estrogen receptor-␣ and estrogen receptor-␤ agonists rapidly decrease pulmonary artery vasoconstriction by a nitric oxide-dependent mechanism. Am J Physiol Regul Integr Comp Physiol 295: R1486 -R1493, 2008. First published October 1, 2008 doi:10.1152/ajpregu.90667.2008.-Both endogenous and exogenous estrogen decrease pulmonary artery (PA) vasoconstriction. Whether these effects are mediated via estrogen receptor (ER)-␣ or ER-␤, and whether the contribution of ERs is stimulus-dependent, remains unknown. We hypothesized that administration of the selective ER-␣ agonist propylpyrazole triol (PPT) and/or the selective ER-␤ agonist diarylpropiolnitrile (DPN) rapidly decreases PA vasoconstriction induced by pharmacologic and hypoxic stimuli via a nitric oxide (NO)-dependent mechanism. PA rings (n ϭ 3-10/group) from adult male Sprague-Dawley rats were suspended in physiologic organ baths. Force displacement was measured. Vasoconstrictor responses to phenylephrine (10 Ϫ8 M Ϫ 10 Ϫ5 M) and hypoxia (PO2 35-45 mmHg) were determined. Endothelium-dependent and -independent vasorelaxation were measured by generating dose-response curves to acetylcholine (10 Ϫ8 M Ϫ 10 Ϫ4 M) and sodium nitroprusside (10 Ϫ9 M Ϫ 10 Ϫ5 M). PPT or DPN (10 Ϫ9 M Ϫ 5 ϫ 10 Ϫ5 M) were added to the organ bath in the presence and absence of the NO-synthase inhibitor N -nitro-L-arginine methyl ester (L-NAME) (10 Ϫ4 M). Selective ER-␣ activation (PPT, 5 ϫ 10 Ϫ5 M) rapidly (Ͻ20 min) decreased phenylephrine-induced vasoconstriction. This effect, as well as PPT's effects on endothelium-dependent vasorelaxation, were neutralized by L-NAME. In contrast, selective ER-␤ activation (DPN, 5 ϫ 10 Ϫ5 M) rapidly decreased phase II of hypoxic pulmonary vasoconstriction (HPV). L-NAME eliminated this phenomenon. Lower PPT or DPN concentrations were less effective. We conclude that both ER-␣ and ER-␤ decrease PA vasoconstriction. The immediate onset of effect suggests a nongenomic mechanism. The contribution of specific ERs appears to be stimulus specific, with ER-␣ primarily modulating phenylephrine-induced vasoconstriction, and ER-␤ inhibiting HPV. NO inhibition eliminates these effects, suggesting a central role for NO in mediating the pulmonary vascular effects of both ER-␣ and ER-␤. propylpyrazole triol; diarylpropiolnitrile; phenylephrine; hypoxic pulmonary vasoconstriction; nongenomic effects FEMALE SEX IS INCREASINGLY recognized as a protective factor in patients suffering from trauma and sepsis (12, 16). The critical role of sex hormones has recently been recognized. In particular, 17␤-estradiol (E2) has been shown to improve outcomes in experimental trauma hemorrhage and shock (13, 14, 41), sepsis (5, 7, 12), myocardial ischemia-reperfusion (39, 40), and acute lung injury (30,35,42). The protective effects of E2 are mediated via estrogen receptor (ER)-␣ and ER-␤. The effects of these ER subtypes are tissue and compartment specific. For example, ER-␣ decreases proinflammatory cytokine production by splenic macrophages and Kupffer cells after traumahemor...

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“…In a CLP model, multiple oral doses of a nonsteroidal selective estrogen receptor-beta agonist increase survival of mice, decrease systemic bacteremia, reduce peritoneal IL-6 and TNF levels. Interestingly, the estrogen receptor-beta agonist provides a comparable level of protection in both males and females (Cristofaro et al, 2006). On another hand, the administration of an estrogen receptor alpha agonist entirely prevents the rise in plasma IL-6 and IL-10 levels induced by a sequence of trauma-hemorrhage whereas the administration of an estrogen receptor beta agonist is only in part effective.…”

Section: Mouse Model Of Sepsismentioning

confidence: 95%

Sex Hormones and Bacterial Infections

Léone¹,

Textoris²,

Capo³

et al. 2012

Sex Hormones

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WAY-202196, a selective estrogen receptor-beta agonist, protects against death in experimental septic shock

Cited by 59 publications

References 33 publications

Targeting estrogen receptor subtypes (ERα and ERβ) with selective ER modulators in ovarian cancer

Targeting estrogen receptor subtypes (ERα and ERβ) with selective ER modulators in ovarian cancer

Selective estrogen receptor-α and estrogen receptor-β agonists rapidly decrease pulmonary artery vasoconstriction by a nitric oxide-dependent mechanism

Sex Hormones and Bacterial Infections

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