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Planta Med
DOI: 10.1055/a-2805-4670
Original Papers

Phaeosphaeride A isolated from an endophytic Paraphoma sp. alleviates ABCG2-mediated resistance to mitoxantrone in breast cancer cells

Authors

  • Alireza Tavakkoli 

    1   Department of Pharmacognosy, Urmia University of Medical Sciences, Urmia, Iran (the Islamic Republic of) (Ringgold ID: RIN37555)

  • Hojjat Mortazavi

    2   Department of Clinical Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran (the Islamic Republic of) (Ringgold ID: RIN37552)

  • mehrdad Iranshahi

    3   Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran (the Islamic Republic of) (Ringgold ID: RIN37552)

  • Fatemeh Kalalinia

    4   Department of Pharmaceutical Biotechnology, Mashhad University of Medical Sciences, Mashhad, Iran (the Islamic Republic of) (Ringgold ID: RIN37552)

  • khadijeh jamialahmadi

    5   Mashhad University of Medical Sciences, Mashhad, Iran (the Islamic Republic of) (Ringgold ID: RIN37552)

  • Jon S. Thorson

    6   Department of Pharmaceutical Sciences, University of Kentucky, Lexington, United States (Ringgold ID: RIN4530)

  • Khaled A. Shaaban 

    7   Department of Pharmaceutical Sciences, University of Kentucky College of Pharmacy, Lexington, United States (Ringgold ID: RIN15511)

  • Fatemeh Mosaffa

    3   Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran (the Islamic Republic of) (Ringgold ID: RIN37552)
    4   Department of Pharmaceutical Biotechnology, Mashhad University of Medical Sciences, Mashhad, Iran (the Islamic Republic of) (Ringgold ID: RIN37552)

Supported by: National Institute of General Medical Sciences P20 GM130456
Supported by: National Institute of Food and Agriculture 2023-38821-39584
Supported by: National Institute of Allergy and Infectious Diseases R37 AI052218
Supported by: National Center for Advancing Translational Sciences UL1TR000117,UL1TR001998
Supported by: Mashhad University of Medical Sciences 4001118
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The efficacy of breast cancer chemotherapies is frequently limited by multidrug resistance (MDR), partly through efflux by ABC transporters, including ABCG2. This study evaluated whether phaeosphaeride A (PPA), a fungal metabolite isolated from a Paraphoma sp. endophyte of Ferula xylorhachis, can modulate ABCG2-mediated resistance to mitoxantrone (MTX). The endophyte was cultured, extracted with ethyl acetate, and purified by chromatography and HPLC to yield PPA, whose structure was confirmed by NMR and MS analyses. Cytotoxicity of MTX, PPA, and their combination was assessed in MCF-7 and ABCG2-overexpressing MCF-7/MX cells. MTX showed marked differential cytotoxicity (IC50 = 1.6 μM, 95% CI: 1.4–1.9 in MCF-7 vs. >25 μM in MCF-7/MX; p < 0.0001), whereas PPA exhibited comparable activity in both lines (23.2 μM, 95% CI: 18.0–30.1 vs. 36.1 μM, 95% CI: 28.7–46.0; p = 0.01). Co-treatment with PPA IC50 significantly reduced MTX IC50 to 0.4 μM (95% CI: 0.3–0.6) in MCF-7, and 1.9 μM (95% CI: 1.2–2.7) in MCF-7/MX, restoring MTX sensitivity in resistant cells to near MCF-7 levels. Flow cytometry showed that PPA (IC50) increased intracellular MTX accumulation with stronger effects in MCF-7/MX cells (p<0.0001) than in MCF-7 (p<0.05). In combination with MTX, PPA (IC50) increased Sub-G1 apoptotic populations in both lines. These findings demonstrate that PPA is unlikely to be a substrate of ABCG2 but functionally inhibits ABCG2-mediated efflux, contributing to the restoration of MTX sensitivity, although there may be additional mechanisms involved. PPA could be a promising MDR-reversal agent in ABCG2-driven chemotherapy resistance.



Publication History

Received: 08 September 2025

Accepted after revision: 04 February 2026

Accepted Manuscript online:
04 February 2026

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