Fatemeh Mosaffa

Bibliography: Planta Medica DOI: 10.1055/a-2805-4670 Art ID: PLAMED-2025-09-0822-OP.R2 Title: Phaeosphaeride A Isolated from an Endophytic Paraphoma sp. Alleviates ABCG2-mediated Resistance to Mitoxantrone in Breast Cancer Cells Published online: 2026-02-25 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG, Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany In the pdf version of the article mentioned above the Contributorʼs Statement and the Funding Information have been incomplete. This was corrected in the pdf version on 12.03.2026. Article published online: 12 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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 and extracted with ethyl acetate, and the extract was purified by column 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. Received: 08 September 2025 Accepted after revision: 03 February 2026 Accepted Manuscript online: 04 February 2026 Article published online: 25 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 14, 70469 Stuttgart, Germany

Background: This study focused on macrocyclic diterpenes derived from Euphorbia, particularly myrsinanes, and their potential in cytotoxic and combination treatments for resistant cancer cells. We examine premyrsinanes isolated from Euphorbia malleata and explore their cytotoxic properties. Methods: Euphorbia malleata was collected from Taragh-Roud, Natanz, Iran. The semi-polar chloroform/acetone extract was chromatographed and fractionated using a large silica column. Fractions containing diterpene resonances were selected based on 1H-NMR spectra and were further subjected to smaller silica or Sephadex columns, followed by a recycling HPLC system. The isolated compounds were identified through 1D and 2D-NMR experiments and mass spectrometry. The cytotoxicity of the isolated compounds was assessed using the MTT assay against A2780 wild and A2780 cisplatin-resistant (R-CIS) cells, both in mono and combination treatments with cisplatin. Results and Conclusions: Using a Waters 616 HPLC pump and a YMC prep silica column, we successfully isolated two new premyrsinane diterpenes (Malleatin A and Malleatin B) alongside two known compounds (beta-sitosterol and loliolide). Malleatin A exhibited cytotoxicity against A2780 wild and A2780 R-CIS cells, with an IC50 range of 50 - 65 μM in the MTT assay. While cisplatin demonstrated significant cytotoxic effects on the A2780 wild cell line, it was ineffective against the A2780 R-CIS cells due to their resistance. However, the combination therapy of Malleatin A and cisplatin exhibited a synergistic effect, significantly increasing the mortality rate of the resistant cells compared to monotherapy. The Combination Index (CI) of 0.58 indicates effective synergy, and the Dose Reduction Index (DRI) of 3.65 suggests a favorable reduction in the dosage of cisplatin needed, potentially reducing its associated side effects.

Background & Objective: Ovarian cancer ranks among the most prevalent gynecologic cancers in women with the majority of patients experiencing a recurrent type and developing treatment resistance. Resistance to chemotherapy drugs has been observed to trigger epithelial-mesenchymal transition (EMT), which leads to the acquisition of metastatic properties. Thus, targeting the molecular ...

Objective(s): Macrophages exhibit versatile phenotypes, with M1 macrophages releasing inflammatory cytokines and possessing microbicidal activities, while M2 macrophages release antiinflammatory cytokines and contribute to tissue repair. The M1/M2 imbalance plays a significant role in various pathological processes. Crocin, known for its antioxidant properties and ability to eliminate free radicals, has been investigated for its potential anti-inflammatory effects. We examined the effect of the primary activation state of macrophages on their phenotype switching when exposed to crocin. Materials and Methods: The crocin impact on macrophage viability was evaluated by MTT. TNF-alpha, IL-6, and IL-10 secretion, as well as Nos2/Arg1 ratio, were measured in cells treated with crocin or LPS+IFN-gamma (M1 inducers), in cells concurrently treated with crocin and LPS+IFN-gamma or in cells pretreated with crocin before M1 induction. Results: Crocin did not show any toxicity at the concentration of 500 mu M or lower. When uncommitted macrophages were exposed to crocin (25-100 mu M), it elevated certain M1 activity indicators, including Nos2/Arg1 ratio and TNF-alpha secretion, but not IL-6. Crocin in concurrent treatment with LPS+IFN-gamma prevented the increase in M1 indicators, Nos2/Arg1 ratio, and TNF-alpha secretion. However, pretreatment of cells with crocin before the addition of LPS+IFN-gamma did not reverse M1 induction in macrophages; instead, it further increased the Nos2/Arg1 ratio and TNF-alpha secretion. IL-10 was not detectable in any of the experimental groups. Conclusion: It appears that the modulatory effects of crocin on macrophage M1/M2 phenotype switching partly depend on the presence or absence of inflammatory mediators and, accordingly, the initial state of macrophage commitment.

Glioblastoma multiforme (GBM), a highly aggressive tumor, poses significant challenges in achieving successful treatment outcomes. Conventional therapeutic modalities including surgery, radiation, and chemotherapy have demonstrated limited efficacy, primarily attributed to the complexities associated with drug delivery to the tumor site and tumor heterogeneity. To address this critical need for innovative therapies, the potential of cancer vaccines utilizing tumor cells and dendritic cells has been explored for GBM treatment. This article provides a comprehensive review of therapeutic vaccinations employing cell-based vaccine strategies for the management of GBM. A meticulous evaluation of 45 clinical trials involving more than 1500 participants revealed that cell-based vaccinations have exhibited favorable safety profiles with minimal toxicity. Moreover, these vaccines have demonstrated modest improvements in overall survival and progression-free survival among patients. However, certain limitations still persist. Notably, there is a need for advancements in the development of potent antigens to evoke immune responses, as well as the optimization of dosage regimens. Consequently, while cell-based vaccinations show promise as a potential therapeutic approach for GBM, further research is imperative to overcome the current limitations. The ultimate objective is to surmount these obstacles and establish cell-based vaccinations as a standard therapeutic modality for GBM.

Cancer endocrine therapy can promote evolutionary dynamics and lead to changes in the gene expression profile of tumor cells. We aimed to assess the effect of tamoxifen (TAM)-resistance induction on ABCG2 pump mRNA, protein, and activity in ER + MCF-7 breast cancer cells. We also evaluated if the resistance to TAM leads to the cross-resistance toward mitoxantrone (MX), a well-known substrate of the ABCG2 pump. The ABCG2 mRNA and protein expression were compared in MCF-7 and its TAM-resistant derivative MCF-7/TAMR cells using RT-qPCR and western blot methods, respectively. Cross-resistance of MCF-7/TAMR cells toward MX was evaluated by the MTT method. Flow cytometry was applied to compare ABCG2 function between cell lines using MX accumulation assay. ABCG2 mRNA expression was also analyzed in tamoxifen-sensitive (TAM-S) and tamoxifen-resistant (TAM-R) breast tumor tissues. The levels of ABCG2 mRNA, protein, and activity were significantly higher in MCF-7/TAMR cells compared to TAM-sensitive MCF-7 cells. MX was also less toxic in MCF-7/TAMR compared to MCF-7 cells. ABCG2 was also upregulated in tissue samples obtained from TAM-R cancer patients compared to TAM-S patients. Prolonged exposure of ER + breast cancer cells to the active form of TAM and clonal evolution imposed by the selective pressure of the drug can lead to higher expression of the ABCG2 pump in the emerged TAM-resistant cells. Therefore, in choosing a sequential therapy for a patient who develops resistance to TAM, the possibility of the cross-resistance of the evolved tumor to chemotherapy drugs that are ABCG2 substrates should be considered. Graphical abstract Prolonged exposure of MCF-7 breast cancer cells to tamoxifen can cause resistance to it and an increase in the expression of the ABCG2 mRNA and protein levels in the cells. Tamoxifen resistance can lead to cross-resistance to mitoxantrone.