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- Publisher Website: 10.1016/j.phymed.2020.153408
- Scopus: eid_2-s2.0-85096476843
- PMID: 33234363
- WOS: WOS:000605579700004
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Article: Synergistic breast cancer suppression efficacy of doxorubicin by combination with glycyrrhetinic acid as an angiogenesis inhibitor
Title | Synergistic breast cancer suppression efficacy of doxorubicin by combination with glycyrrhetinic acid as an angiogenesis inhibitor |
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Authors | |
Keywords | Doxorubicin Glycyrrhetinic acid Combination Angiogenesis Breast cancer |
Issue Date | 2021 |
Publisher | Elsevier GmbH - Urban und Fischer Verlag. The Journal's web site is located at http://www.elsevier.com/locate/phytomed |
Citation | Phytomedicine, 2021, v. 81, article no. 153408 How to Cite? |
Abstract | Background: Therapeutic regimens of breast cancer treatment are increasingly inclined to adopt combination strategy based on the broad spectrum antitumor effect of doxorubicin (Dox). Currently, combination therapy comprises of conventional anti-cancer drugs and angiogenesis inhibitors have been corroborated as an effective approach in cancer treatment.
Purpose: We explored the ability of a natural anti-angiogenic compound glycyrrhetinic acid (GA), derived from an edible-medicinal herb licorice, to enhance the breast cancer suppression effect of Dox.
Study design: The drug ratio of GA and Dox with synergistic anticancer effect against MCF-7 cells was optimized by combination index (CI) value in vitro, followed by evaluation of the improved anticancer effects and reduced side-effects of this combination in vitro and in vivo. Methods: Cell viability was measured by MTT assay. Analyses of mitochondrial membrane potential and cell apoptosis on MCF-7 cells were performed by JC-1 dye and Annexin V-FITC/PI assays. The cellular accumulation of Dox when combined with GA was evaluated. Levels of apoptosis-related proteins in MCF-7 cells were measured by Western blot analysis. Synergistic anti-angiogenic effects on HUVECs were evaluated. A breast cancer mouse model was established to investigate the anti-tumor effects in vivo.
Results: Based on the optimization by CI value, Dox and GA at 1:20 molar ratio was chosen as the optimal combination drug ratio that exhibited synergistic effect against MCF-7 breast cancer cells. In addition, the combination of GA and Dox exhibited significantly enhanced cytotoxicity, apoptosis, and loss of mitochondrial membrane potential via the upregulation of a mitochondrial-dependent apoptosis pathway against MCF-7 cells. Interestingly, the addition of GA increased the intracellular accumulation of Dox in MCF-7 cells. Moreover, VEGF-induced HUVECs proliferation, migration, and tube formation were strongly inhibited by Dox when used with GA via the significant down-regulation of VEGFR2-mediated pathway, indicating that the combination of Dox and GA could exhibit ideal synergistic anti-angiogenesis effect. Expectedly, the enhanced anti-tumor efficacy of Dox and reduced Dox-induced cardiotoxicity when used in combination with GA were evident in a mouse breast tumor model.
Conclusions: These findings support that the combination of Dox with GA is a novel and promising therapeutic strategy for the treatment of breast cancer. |
Persistent Identifier | http://hdl.handle.net/10722/294857 |
ISSN | 2021 Impact Factor: 6.656 2020 SCImago Journal Rankings: 1.045 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Shi, J | - |
dc.contributor.author | Li, J | - |
dc.contributor.author | Li, J | - |
dc.contributor.author | LI, R | - |
dc.contributor.author | Wu, X | - |
dc.contributor.author | Gao, F | - |
dc.contributor.author | Zou, L | - |
dc.contributor.author | MAK, WWS | - |
dc.contributor.author | Fu, C | - |
dc.contributor.author | Zhang, J | - |
dc.contributor.author | Leung, GPH | - |
dc.date.accessioned | 2020-12-21T11:49:32Z | - |
dc.date.available | 2020-12-21T11:49:32Z | - |
dc.date.issued | 2021 | - |
dc.identifier.citation | Phytomedicine, 2021, v. 81, article no. 153408 | - |
dc.identifier.issn | 0944-7113 | - |
dc.identifier.uri | http://hdl.handle.net/10722/294857 | - |
dc.description.abstract | Background: Therapeutic regimens of breast cancer treatment are increasingly inclined to adopt combination strategy based on the broad spectrum antitumor effect of doxorubicin (Dox). Currently, combination therapy comprises of conventional anti-cancer drugs and angiogenesis inhibitors have been corroborated as an effective approach in cancer treatment. Purpose: We explored the ability of a natural anti-angiogenic compound glycyrrhetinic acid (GA), derived from an edible-medicinal herb licorice, to enhance the breast cancer suppression effect of Dox. Study design: The drug ratio of GA and Dox with synergistic anticancer effect against MCF-7 cells was optimized by combination index (CI) value in vitro, followed by evaluation of the improved anticancer effects and reduced side-effects of this combination in vitro and in vivo. Methods: Cell viability was measured by MTT assay. Analyses of mitochondrial membrane potential and cell apoptosis on MCF-7 cells were performed by JC-1 dye and Annexin V-FITC/PI assays. The cellular accumulation of Dox when combined with GA was evaluated. Levels of apoptosis-related proteins in MCF-7 cells were measured by Western blot analysis. Synergistic anti-angiogenic effects on HUVECs were evaluated. A breast cancer mouse model was established to investigate the anti-tumor effects in vivo. Results: Based on the optimization by CI value, Dox and GA at 1:20 molar ratio was chosen as the optimal combination drug ratio that exhibited synergistic effect against MCF-7 breast cancer cells. In addition, the combination of GA and Dox exhibited significantly enhanced cytotoxicity, apoptosis, and loss of mitochondrial membrane potential via the upregulation of a mitochondrial-dependent apoptosis pathway against MCF-7 cells. Interestingly, the addition of GA increased the intracellular accumulation of Dox in MCF-7 cells. Moreover, VEGF-induced HUVECs proliferation, migration, and tube formation were strongly inhibited by Dox when used with GA via the significant down-regulation of VEGFR2-mediated pathway, indicating that the combination of Dox and GA could exhibit ideal synergistic anti-angiogenesis effect. Expectedly, the enhanced anti-tumor efficacy of Dox and reduced Dox-induced cardiotoxicity when used in combination with GA were evident in a mouse breast tumor model. Conclusions: These findings support that the combination of Dox with GA is a novel and promising therapeutic strategy for the treatment of breast cancer. | - |
dc.language | eng | - |
dc.publisher | Elsevier GmbH - Urban und Fischer Verlag. The Journal's web site is located at http://www.elsevier.com/locate/phytomed | - |
dc.relation.ispartof | Phytomedicine | - |
dc.subject | Doxorubicin | - |
dc.subject | Glycyrrhetinic acid | - |
dc.subject | Combination | - |
dc.subject | Angiogenesis | - |
dc.subject | Breast cancer | - |
dc.title | Synergistic breast cancer suppression efficacy of doxorubicin by combination with glycyrrhetinic acid as an angiogenesis inhibitor | - |
dc.type | Article | - |
dc.identifier.email | Li, J: kimli07@hku.hk | - |
dc.identifier.email | Wu, X: raxpwu@hku.hk | - |
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.phymed.2020.153408 | - |
dc.identifier.pmid | 33234363 | - |
dc.identifier.scopus | eid_2-s2.0-85096476843 | - |
dc.identifier.hkuros | 320687 | - |
dc.identifier.volume | 81 | - |
dc.identifier.spage | article no. 153408 | - |
dc.identifier.epage | article no. 153408 | - |
dc.identifier.isi | WOS:000605579700004 | - |
dc.publisher.place | Germany | - |