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Research Article

Bioinformatics and In vitro Studies Reveal the Importance of p53, PPARG and Notch Signaling Pathway in Inhibition of Breast Cancer Stem Cells by Hesperetin

Adam Hermawan 1,2* ORCID logo, Muthi Ikawati 1,2, Annisa Khumaira 2, Herwandhani Putri 2, Riris Istighfari Jenie 1,2, Sonia Meta Angraini 2, Haruma Anggraini Muflikhasari 2

1 Laboratory of Macromolecular Engineering, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, 55281 Yogyakarta, Indonesia.
2 Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, 55281 Yogyakarta, Indonesia.

Abstract

Purpose: The failure of chemotherapy in breast cancer is caused by breast cancer stem cells (BCSCs), a minor population of cells in bulk mammary tumors. Previously, hesperetin, a citrus flavonoid, showed cytotoxicity in several cancer cells and increased cytotoxicity of doxorubicin and cisplatin. Hesperetin also inhibited osteogenic and adipocyte differentiation, however, a study of the effect of hesperetin on BCSCs has not yet been performed.
Methods: In this study, we combined bioinformatics and in vitro work. A bioinformatic approach was performed to identify molecular targets, key proteins, and molecular mechanisms of hesperetin targeted at BCSCs, and genetic alterations among key genes. In addition, an in vitro study was carried out to measure the effects of hesperetin on BCSCs using the spheroids model of MCF-7 breast cancer cells (mammospheres).
Results: Using a bioinformatics approach, we identified P53, PPARG, and Notch signaling as potential targets of hesperetin in inhibition of BCSCs. The in vitro study showed that hesperetin exhibits cytotoxicity on mammospheres inhibits mammosphere and colony formation, and inhibits migration. Hesperetin modulates the cell cycle and induces apoptosis in mammospheres. Moreover, hesperetin treatment modulates the expression of p53, PPARG, and NOTCH1.
Conclusion: Taken together, hesperetin has potential for the treatment of BCSC by targeting p53, PPARG and Notch signaling. Further investigation of the molecular mechanisms involved is required for the development of hesperetin as a BCSC-targeted drug.
Keywords: Hesperetin, Breast cancer stem cells, Bioinformatics, in vitro, Mammosphere, Targeted therapy
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Submitted: 15 Feb 2020
Revision: 16 Apr 2020
Accepted: 19 Apr 2020
ePublished: 19 Apr 2020
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