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Article: Oridonin synergistically enhances the anti-tumor efficacy of doxorubicin against aggressive breast cancer via pro-apoptotic and anti-angiogenic effects

TitleOridonin synergistically enhances the anti-tumor efficacy of doxorubicin against aggressive breast cancer via pro-apoptotic and anti-angiogenic effects
Authors
KeywordsBreast cancer
Oridonin
Doxorubicin
Angiogenesis
Cardioprotection
Issue Date2019
PublisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/issn/10436618
Citation
Pharmacological Research, 2019, v. 146, article no. 104313 How to Cite?
AbstractThe therapeutic outcomes of doxorubicin (Dox) treatment in breast cancer are limited by decreased drug efficiency and cardiotoxicity. The aim of this study was to investigate whether oridonin (Ori), a natural chemical abundant in the Chinese herb Isodon rubescens, might potentiate the anticancer effects, and decrease the adverse cardiotoxic effects, of Dox. On the basis of the optimized drug ratio determined through combination index calculations, we evaluated the synergistic effects and potential mechanisms of combining Dox with Ori to suppress breast cancer growth and angiogenesis both in vitro and in vivo. Dox plus Ori synergistically induced apoptosis in MDA-MB-231 cells, in a manner involving regulation of the Bcl-2/Bax, PARP, Caspase 3 and Survivin signaling pathways. Additionally, Ori increased the intracellular accumulation of Dox in MDA-MB-231 cells. Moreover, Dox plus Ori significantly decreased the proliferation, migration, invasion and tube formation of HUVECs. The underlying anti-angiogenic mechanism may have been due to the inhibition of VEGFR2-mediated signaling. Computational docking analysis further demonstrated that Dox plus Ori had high affinity toward the ATP-binding domain of VEGFR-2 kinase. Consistently with these findings, in vivo studies indicated that Ori enhanced the antitumor effect of Dox via activating apoptosis and inhibiting blood vessel formation at tumor sites. Moreover, Ori reversed the Dox-induced cardiotoxicity in a mouse model. In conclusion, our findings provide strong evidence that Ori may be highly promising in enhancing the efficacy of Dox and decreasing its adverse cardiotoxic effects, thus suggesting that Ori may serve as a potential adjunct therapy during Dox-based chemotherapy.
Persistent Identifierhttp://hdl.handle.net/10722/272293
ISSN
2017 Impact Factor: 4.897
2015 SCImago Journal Rankings: 2.108

 

DC FieldValueLanguage
dc.contributor.authorLi, J-
dc.contributor.authorWu, Y-
dc.contributor.authorWang, D-
dc.contributor.authorZou, L-
dc.contributor.authorFu, C-
dc.contributor.authorZhang, J-
dc.contributor.authorLeung, GPH-
dc.date.accessioned2019-07-20T10:39:26Z-
dc.date.available2019-07-20T10:39:26Z-
dc.date.issued2019-
dc.identifier.citationPharmacological Research, 2019, v. 146, article no. 104313-
dc.identifier.issn1043-6618-
dc.identifier.urihttp://hdl.handle.net/10722/272293-
dc.description.abstractThe therapeutic outcomes of doxorubicin (Dox) treatment in breast cancer are limited by decreased drug efficiency and cardiotoxicity. The aim of this study was to investigate whether oridonin (Ori), a natural chemical abundant in the Chinese herb Isodon rubescens, might potentiate the anticancer effects, and decrease the adverse cardiotoxic effects, of Dox. On the basis of the optimized drug ratio determined through combination index calculations, we evaluated the synergistic effects and potential mechanisms of combining Dox with Ori to suppress breast cancer growth and angiogenesis both in vitro and in vivo. Dox plus Ori synergistically induced apoptosis in MDA-MB-231 cells, in a manner involving regulation of the Bcl-2/Bax, PARP, Caspase 3 and Survivin signaling pathways. Additionally, Ori increased the intracellular accumulation of Dox in MDA-MB-231 cells. Moreover, Dox plus Ori significantly decreased the proliferation, migration, invasion and tube formation of HUVECs. The underlying anti-angiogenic mechanism may have been due to the inhibition of VEGFR2-mediated signaling. Computational docking analysis further demonstrated that Dox plus Ori had high affinity toward the ATP-binding domain of VEGFR-2 kinase. Consistently with these findings, in vivo studies indicated that Ori enhanced the antitumor effect of Dox via activating apoptosis and inhibiting blood vessel formation at tumor sites. Moreover, Ori reversed the Dox-induced cardiotoxicity in a mouse model. In conclusion, our findings provide strong evidence that Ori may be highly promising in enhancing the efficacy of Dox and decreasing its adverse cardiotoxic effects, thus suggesting that Ori may serve as a potential adjunct therapy during Dox-based chemotherapy.-
dc.languageeng-
dc.publisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/issn/10436618-
dc.relation.ispartofPharmacological Research-
dc.subjectBreast cancer-
dc.subjectOridonin-
dc.subjectDoxorubicin-
dc.subjectAngiogenesis-
dc.subjectCardioprotection-
dc.titleOridonin synergistically enhances the anti-tumor efficacy of doxorubicin against aggressive breast cancer via pro-apoptotic and anti-angiogenic effects-
dc.typeArticle-
dc.identifier.emailLeung, GPH: gphleung@hkucc.hku.hk-
dc.identifier.authorityLeung, GPH=rp00234-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.phrs.2019.104313-
dc.identifier.pmid31202781-
dc.identifier.scopuseid_2-s2.0-85067303996-
dc.identifier.hkuros298339-
dc.identifier.volume146-
dc.identifier.spagearticle no. 104313-
dc.identifier.epagearticle no. 104313-
dc.publisher.placeUnited Kingdom-

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