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Article: Targeting estrogen receptor subtypes (ERalpha and ERbeta) with selective ER modulators in ovarian cancer

TitleTargeting estrogen receptor subtypes (ERalpha and ERbeta) with selective ER modulators in ovarian cancer
Authors
Issue Date2014
PublisherBioscientifica Ltd. The Journal's web site is located at http://joe.endocrinology-journals.org
Citation
Journal of Endocrinology, 2014, v. 221, p. 325-336 How to Cite?
AbstractOvarian cancer cells express both estrogen receptor α (ERα) and ERβ, 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 ERα compared with ERβ, 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. Sodium 3′-(1-(phenylaminocarbonyl)-3,4-tetrazolium)-bis(4-methoxy-6-nitro) benzene sulfonic acid hydrate (XTT) assay revealed that treatment with 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride (MPP) (ERα antagonist) or 2,3-bis(4-hydroxy-phenyl)-propionitrile (DPN) (ERβ agonist) significantly suppressed cell growth in both cell lines. In contrast, 4,4′,4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT) (ERα agonist) or 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]-pyrimidin-3-yl]phenol (PHTPP) (ERβ antagonist) significantly enhanced cell growth. 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.
Persistent Identifierhttp://hdl.handle.net/10722/197656

 

DC FieldValueLanguage
dc.contributor.authorChan, KKLen_US
dc.contributor.authorLeung, THYen_US
dc.contributor.authorChan, DWen_US
dc.contributor.authorWEI, Nen_US
dc.contributor.authorLau, TYen_US
dc.contributor.authorLiu, Sen_US
dc.contributor.authorSiu, KYen_US
dc.contributor.authorNgan, HYSen_US
dc.date.accessioned2014-05-29T08:36:51Z-
dc.date.available2014-05-29T08:36:51Z-
dc.date.issued2014en_US
dc.identifier.citationJournal of Endocrinology, 2014, v. 221, p. 325-336en_US
dc.identifier.urihttp://hdl.handle.net/10722/197656-
dc.description.abstractOvarian cancer cells express both estrogen receptor α (ERα) and ERβ, 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 ERα compared with ERβ, 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. Sodium 3′-(1-(phenylaminocarbonyl)-3,4-tetrazolium)-bis(4-methoxy-6-nitro) benzene sulfonic acid hydrate (XTT) assay revealed that treatment with 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride (MPP) (ERα antagonist) or 2,3-bis(4-hydroxy-phenyl)-propionitrile (DPN) (ERβ agonist) significantly suppressed cell growth in both cell lines. In contrast, 4,4′,4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT) (ERα agonist) or 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]-pyrimidin-3-yl]phenol (PHTPP) (ERβ antagonist) significantly enhanced cell growth. 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.en_US
dc.languageengen_US
dc.publisherBioscientifica Ltd. The Journal's web site is located at http://joe.endocrinology-journals.orgen_US
dc.relation.ispartofJournal of Endocrinologyen_US
dc.titleTargeting estrogen receptor subtypes (ERalpha and ERbeta) with selective ER modulators in ovarian canceren_US
dc.typeArticleen_US
dc.identifier.emailChan, KKL: kklchan@hkucc.hku.hken_US
dc.identifier.emailLeung, THY: thyl@hku.hken_US
dc.identifier.emailChan, DW: dwchan@hku.hken_US
dc.identifier.emailLau, TY: ecargual@hku.hken_US
dc.identifier.emailLiu, S: stephasl@hku.hken_US
dc.identifier.emailSiu, KY: mkysiu@hkucc.hku.hken_US
dc.identifier.emailNgan, HYS: hysngan@hkucc.hku.hken_US
dc.identifier.authorityChan, KKL=rp00499en_US
dc.identifier.authorityChan, DW=rp00543en_US
dc.identifier.authorityLiu, S=rp00372en_US
dc.identifier.authoritySiu, KY=rp00275en_US
dc.identifier.authorityNgan, HYS=rp00346en_US
dc.identifier.hkuros228888en_US
dc.identifier.volume221en_US
dc.identifier.spage325en_US
dc.identifier.epage336en_US
dc.publisher.placeGreat Britainen_US

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