Isoeugenol-derived polyphenolic compounds modulate FOLFOX response, drug resistance, migration, and stemness-associated signatures in HT29 colon cancer cells and an HT29-CSC-enriched population.

Authors

Sema Bilgin, Yahya Tayhan, Şeyma Yaşar, Seçil Erden Tayhan, Aslı Yıldırım Kocaman, Esra Koç

Published in

Bioorganic chemistry. Volume 185. Pages 110714. Nov 06, 2026. Epub Nov 06, 2026.

Abstract

Chemoresistance, cancer stem cell-associated plasticity, and migratory capacity limit the efficacy of FOLFOX-based chemotherapy in colon cancer. This study investigated the effects of two original isoeugenol-derived polyphenolic compounds, 1 and 2, alone and in combination with FOLFOX, in HT29 colon cancer cells and an HT29-derived cancer stem cell-enriched population. Cell viability was assessed by MTT assay, drug interactions were evaluated using the Chou-Talalay combination index method, wound closure was analyzed by scratch assay, and multidrug resistance-, stemness-, and migration/metastasis-associated gene expression profiles were examined by real-time quantitative polymerase chain reaction. Molecular docking was performed against selected proteins related to drug transport, extracellular matrix remodeling, angiogenesis, and cancer stem cell biology. In HT29 cells, the half-maximal inhibitory concentration (IC₅₀) of FOLFOX decreased from 191.80 μM at 24 h to 15.52 μM at 48 h, while FOLFOX +1 and FOLFOX +2 further reduced the 48-h IC₅₀ values to 13.30 and 14.95 μM, respectively. In the HT29-CSC-enriched population, FOLFOX showed a 48-h IC₅₀ of 26.80 μM, whereas FOLFOX +2 produced the lowest IC₅₀ value among all groups (17.97 μM). Both combinations showed synergistic interactions in cell viability response particularly at moderate effect levels. FOLFOX +2 consistently reduced wound closure in both cellular models. Gene expression analyses revealed target- and cell model-dependent modulation of drug transporter-, stemness-, and migration/metastasis-associated genes rather than uniform suppression. Docking analyses supported the predicted interaction potential of compounds 1 and 2 with multiple cancer-related targets. Overall, these findings suggest that isoeugenol-derived polyphenolic compounds may modulate FOLFOX-associated responses through cell viability-related, migration-related, multidrug resistance-associated, and stemness-linked mechanisms.

PMID:
43003048
Bibliographic data and abstract were imported from PubMed on 10 Nov 2026.

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