Phyto-Sesquiterpene Lactones Prevent the Development of Multidrug Resistance in TNBC via ABC Transporters Inhibition and STAT3/MYC Signaling
1
Department of Pharmacy, College of Pharmacy, China Medical University, Taichung 406040, Taiwan
2
School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
3
Department of Pharmacology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
4
Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
5
Department of Pharmacy, China Medical University Hospital, Taichung 404327, Taiwan
6
Department of Healthcare Administration, Asia University, Taichung 41354, Taiwan
*
Author to whom correspondence should be addressed.
Cancers 2025, 17(8), 1321; https://doi.org/10.3390/cancers17081321
Submission received: 4 March 2025
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Revised: 7 April 2025
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Accepted: 11 April 2025
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Published: 14 April 2025
(This article belongs to the Section Cancer Drug Development)
Simple Summary
Triple-negative breast cancer is an aggressive form of breast cancer that lacks effective targeted therapies, making chemotherapy the primary treatment option. However, many patients develop resistance to chemotherapy over time, limiting its effectiveness. MYC, a key oncogene, and STAT3 signaling have been linked to Triple-negative breast cancer progression and treatment resistance. Additionally, multidrug resistance caused by ATP-binding cassette transporters reduces the effectiveness of chemotherapy drugs. Natural compounds, such as sesquiterpene lactones, have shown potential in targeting cancer cells while minimizing toxicity. Helenalin and its derivatives, bis(helenalinyl)malonate and bis(helenalinyl)glutarate, have demonstrated anticancer properties in other cancers, but their effects on triple-negative breast cancer and multidrug resistance remain unclear. This study aims to evaluate the impact of helenalin, bis(helenalinyl)malonate, and bis(helenalinyl)glutarate on triple-negative breast cancer growth and drug resistance, providing insights into their potential as novel therapeutic options.
Abstract
Background: Multidrug resistance (MDR) in triple-negative breast cancer (TNBC) leads to treatment failure and tumor recurrence. Dysregulation of the MYC oncogene is associated with the pathogenesis of TNBC and the development of chemoresistance via overexpression of ATP-binding cassette (ABC) transporters. Therefore, in the present study, we aimed to identify molecules from a natural product origin that prevent the development of MDR in TNBC by targeting the MYC signaling. Methods: The cell viability of TNBC was evaluated using sulforhodamine assay. Protein levels were detected by western blots or enzyme-linked immunosorbent assays. Intracellular calcein and hoechst33342 accumulation assay aimed to evaluate the inhibitory ability of phytocompounds on drug-efflux functions of ABCB1 and ABCG2 transporters. The Cancer Genome Atlas (TCGA) database was used to explore clinical genomic data. Furthermore, the zebrafish xenotransplantation model bearing Dil-labeled TNBC cells was applied to testify the in vivo effects of phyto-sesquiterpene lactones. Results: The results of the present study demonstrated that the phyto-sesquiterpene lactones exhibited an MDR prevention effect by repressing efflux activities of ABCB1 and ABCG2 transporters. Mechanistic studies showed that phyto-sesquiterpene lactones inducted TNBC cell apoptosis and cell cycle G2/M arrested by blocking the STAT3/MYC pathway. Clinical genomic data demonstrated that the percentages of MYC amplification and mRNA were upregulated approximately two-fold higher in the TNBC patients than the non-TNBC breast cancer patients. The survival of patients with an alteration in MYC was significantly lower in TNBC as compared to other subtypes. Moreover, the results of the zebrafish xenograft model confirmed that phyto-sesquiterpene lactones exerted stronger inhibitory effects on TNBC tumor growth in vivo. Conclusions: In conclusion, these three phyto-sesquiterpene lactones were promising candidates for TNBC treatment and shed light on the prevention of developing MDR TNBC.
Keywords:
triple-negative breast cancer; multidrug resistance; ABCB1; ABCG2; MYC; STAT3
