Synergistic breast cancer suppression efficacy of doxorubicin by combination with glycyrrhetinic acid as an angiogenesis inhibitor.

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.

• Authors: Jinfeng Shi, Jingjing Li, Jiaxin Li, Renkai Li, Xiaoping Wu, Fei Gao, Liang Zou, Winston Wing Shum Mak, Chaomei Fu, Jinming Zhang, George Pak-Heng Leung
• Journal: Phytomedicine : international journal of phytotherapy and phytopharmacology (Phytomedicine) Vol. 81 Pg. 153408 (Jan 2021) ISSN: 1618-095X [Electronic] Germany
• PMID: 33234363 (Publication Type: Journal Article)
• Copyright: Copyright © 2020. Published by Elsevier GmbH.

Chemical References

• Angiogenesis Inhibitors
• Doxorubicin
• KDR protein, human
• Vascular Endothelial Growth Factor Receptor-2
• Glycyrrhetinic Acid

Topics

• Angiogenesis Inhibitors (administration & dosage, pharmacology)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects, physiology)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cardiotoxicity (etiology, prevention & control)
• Doxorubicin (administration & dosage, adverse effects)
• Female
• Glycyrrhetinic Acid (administration & dosage)
• Human Umbilical Vein Endothelial Cells
• Humans
• MCF-7 Cells
• Membrane Potential, Mitochondrial (drug effects)
• Mice, Inbred BALB C
• Vascular Endothelial Growth Factor Receptor-2 (metabolism)
• Xenograft Model Antitumor Assays