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- Publisher Website: 10.1016/j.phrs.2019.104313
- Scopus: eid_2-s2.0-85067303996
- PMID: 31202781
- WOS: WOS:000482248300027
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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
Title | Oridonin synergistically enhances the anti-tumor efficacy of doxorubicin against aggressive breast cancer via pro-apoptotic and anti-angiogenic effects |
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Authors | |
Keywords | Breast cancer Oridonin Doxorubicin Angiogenesis Cardioprotection |
Issue Date | 2019 |
Publisher | Academic 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? |
Abstract | The 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 Identifier | http://hdl.handle.net/10722/272293 |
ISSN | 2023 Impact Factor: 9.1 2023 SCImago Journal Rankings: 2.160 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Li, J | - |
dc.contributor.author | Wu, Y | - |
dc.contributor.author | Wang, D | - |
dc.contributor.author | Zou, L | - |
dc.contributor.author | Fu, C | - |
dc.contributor.author | Zhang, J | - |
dc.contributor.author | Leung, GPH | - |
dc.date.accessioned | 2019-07-20T10:39:26Z | - |
dc.date.available | 2019-07-20T10:39:26Z | - |
dc.date.issued | 2019 | - |
dc.identifier.citation | Pharmacological Research, 2019, v. 146, article no. 104313 | - |
dc.identifier.issn | 1043-6618 | - |
dc.identifier.uri | http://hdl.handle.net/10722/272293 | - |
dc.description.abstract | The 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.language | eng | - |
dc.publisher | Academic Press. The Journal's web site is located at http://www.elsevier.com/locate/issn/10436618 | - |
dc.relation.ispartof | Pharmacological Research | - |
dc.subject | Breast cancer | - |
dc.subject | Oridonin | - |
dc.subject | Doxorubicin | - |
dc.subject | Angiogenesis | - |
dc.subject | Cardioprotection | - |
dc.title | Oridonin synergistically enhances the anti-tumor efficacy of doxorubicin against aggressive breast cancer via pro-apoptotic and anti-angiogenic effects | - |
dc.type | Article | - |
dc.identifier.email | Leung, GPH: gphleung@hkucc.hku.hk | - |
dc.identifier.authority | Leung, GPH=rp00234 | - |
dc.description.nature | link_to_subscribed_fulltext | - |
dc.identifier.doi | 10.1016/j.phrs.2019.104313 | - |
dc.identifier.pmid | 31202781 | - |
dc.identifier.scopus | eid_2-s2.0-85067303996 | - |
dc.identifier.hkuros | 298339 | - |
dc.identifier.volume | 146 | - |
dc.identifier.spage | article no. 104313 | - |
dc.identifier.epage | article no. 104313 | - |
dc.identifier.isi | WOS:000482248300027 | - |
dc.publisher.place | United Kingdom | - |
dc.identifier.issnl | 1043-6618 | - |