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Co-delivery of shikonin and JQ1 inhibits triple-negative breast tumor progression and lung metastasis through inhibition of epithelial-mesenchymal transition and vasculogenic mimicry

Acta Pharmacologica Sinica (2025)Cite this article

Abstract

Triple-negative breast cancer (TNBC) is highly prone to lung metastasis, primarily driven by epithelial-mesenchymal transition (EMT) and vasculogenic mimicry (VM). Therefore, inhibiting EMT and VM represents a promising therapeutic strategy for TNBC. The immunosuppressive tumor microenvironment contributes substantially to poor treatment outcomes, with M2-type macrophages secreting excessive levels of TGF-β that promote both EMT and VM. In this study, we proposed a combination therapy strategy involving shikonin (SHK) and JQ1 delivered via a mesoporous polydopamine-based Pickering emulsion (termed MPDA@PE). This formulation significantly suppressed tumor growth and lung metastasis by inducing apoptosis in TNBC and inhibiting TGF-β-induced EMT and VM. Furthermore, MPDA@PE can be incorporated into a thermosensitive hydrogel for application in the prevention of TNBC recurrence and lung metastasis following surgical resection. These findings highlight a potential therapeutic approach for effective TNBC treatment.

The combined administration of SHK and JQ1 inhibits both EMT and VM. This approach disrupts the nutrient supply in tumor tissues by blocking VM and suppresses tumor metastasis through EMT inhibition. Consequently, it demonstrates therapeutic efficacy against TNBC recurrence post-surgery and effectively limits lung metastasis.

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Fig. 1: Preparation and characterization of MPDA@PE.
Fig. 2: Optimized ratio for the combination of SHK and JQ1.
Fig. 3: MPDA@PE induced apoptosis and ICD in 4T1 cells.
Fig. 4: MPDA@PE inhibited M2 macrophages and suppressed TGF-β-mediated EMT and VM.
Fig. 5: MPDA@PE inhibits tumor growth in vivo.
Fig. 6: MPDA@PE induced apoptosis and inhibited EMT and VM in tumor tissues.
Fig. 7: The preparation and characterization of PE@Hydrogel.
Fig. 8: PE@Hydrogel suppressed postoperative tumor recurrence and metastasis in vivo.

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Acknowledgements

We are grateful for the support from the National Key Research and Development Program of China (2024YFA1210200, China), National Natural Science Foundation of China (82341232), Natural Science Foundation of Shanghai Municipal (24ZR1477500), High-level Innovative Research Institute (2021B0909050003) from Department of Science and Technology of Guangdong Province, and Zhongshan Municipal Bureau of Science and Technology (LJ2021001 & CXTD2022011). We thank the staff members of the Large-scale Protein Preparation System (https://cstr.cn/31129.02.NFPS.LSPS) at the National Facility for Protein Science in Shanghai (https://cstr.cn/31129.02.NFPS), for providing technical support and assistance in data collection and analysis in transmission electron microscopy and fluorescence microscope.

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  1. These authors contributed equally: Xing-yu Xu, Dipika Ramdas Kalambhe

Authors and Affiliations

  1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Xing-yu Xu, Dipika Ramdas Kalambhe, Yue Yu, Ling-xi Yu, Zhi-wen Gu, Xiao-ying Jin, Hui-yuan Wang & Yong-zhuo Huang

  2. University of Chinese Academy of Sciences, Beijing, 100049, China

    Xing-yu Xu, Dipika Ramdas Kalambhe, Yue Yu, Ling-xi Yu, Xiao-ying Jin & Yong-zhuo Huang

  3. School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China

    Zhi-wen Gu

  4. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Zhongshan, 528437, China

    Yong-zhuo Huang

  5. NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients, Shanghai, 201203, China

    Yong-zhuo Huang

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Contributions

XYX: Writing – original draft, Methodology, Investigation, Formal analysis, Data curation. DRK: Writing – original draft, Methodology, Investigation, Data curation. YY: Methodology, Investigation. LXY: Methodology, Investigation. ZWG: Methodology, Investigation. XYJ: Methodology, Investigation. HYW: Methodology, Conceptualization. YZH: Writing – review & editing, Writing – original draft, Supervision, Project administration, Funding acquisition, Formal analysis, Conceptualization.

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Correspondence to Hui-yuan Wang or Yong-zhuo Huang.

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Xu, Xy., Kalambhe, D.R., Yu, Y. et al. Co-delivery of shikonin and JQ1 inhibits triple-negative breast tumor progression and lung metastasis through inhibition of epithelial-mesenchymal transition and vasculogenic mimicry. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01605-8

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