Adv Pharm Bull. 2018;8(3): 507-516.
doi: 10.15171/apb.2018.059
PMID: 30276148
PMCID: PMC6156471
Scopus ID: 85052581155
  Abstract View: 3023
  PDF Download: 1370

Research Article

The Cytotoxic and Antimigratory Activity of Brazilin-Doxorubicin on MCF-7/HER2 Cells

Riris Istighfari Jenie 1,2 ORCID logo, Sri Handayani 2,3 ORCID logo, Ratna Asmah Susidarti 1,2, Linar Zalinar Udin 3, Edy Meiyanto 1,2* ORCID logo

1 Departement of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada, Indonesia.
2 Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada, Indonesia.
3 Research Center for Chemistry, Indonesian Institute of Sciences (LIPI), Indonesia.
*Corresponding Author: Email: meiyan_e@ugm.ac.id


Purpose: Breast cancer cells with overexpression of HER2 are known to be more aggressive, invasive, and resistant to chemotherapeutic agent. Brazilin, the major compound in the Caesalpinia sappan L. (CS) heartwood, has been studied for it's anticancer activity. The purpose of this study was to investigate the cytotoxic and antimigratory activity of brazilin (Bi) in combination with doxorubicin (Dox) on MCF-7/HER2 cells. Methods: Cytotoxic activities of Bi individually and in combination with Dox were examined by MTT assay. Synergistic effects were analyzed by combination index (CI). Apoptosis and cell cycle profiles were observed by using flow cytometry. Migrating and invading cells were observed by using a Boyden chamber assay. Levels of MMP2 and MMP9 activity were observed by using a gelatin zymography assay. Levels of HER2, Bcl-2, Rac1, and p120 protein expression were observed by using an immunoblotting assay. Results: The results of the MTT assay showed that Bi inhibited MCF-7/HER2 cell growth in a dose-dependent manner with an IC50 of 54 ± 3.7 µM. Furthermore, the combination of Bi and Dox showed a synergistic effect (CI <1). Flow cytometric analysis of Bi and its combination with Dox showed cellular accumulation in the G2/M phase and induction of apoptosis through suppression of Bcl-2 protein expression. In the Boyden chamber assay, gelatin zymography, and subsequent immunoblotting assay, the combination Bi and Dox inhibited migration, possibly through downregulation of MMP9, MMP2, HER2, Rac1, and p120 protein expression. Conclusion: We conclude that Bi enhanced cytotoxic activity of Dox and inhibited migration of MCF-7/HER2 cells. Therefore, we believe that it has strong potential to be developed for the treatment of metastatic breast cancer with HER2 overexpression.
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Submitted: 16 Feb 2018
Revision: 16 Jul 2018
Accepted: 19 Jul 2018
ePublished: 29 Aug 2018
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