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Evaluating Polyphenol Derivatives on Cancer Stem Cells Using Two- and Three-dimensional Tumoroid Models: Insights
Sema Bilgin1, Seçil Erden Tayhan2, Şeyma Yaşar3
1Department of Medical Laboratory Techniques, Vocational School of Health Services, Tokat Gaziosmanpasa University, Tokat, Turkey.
Abstract:
Cancer stem cells (CSCs) drive tumor initiation, metastasis, drug resistance, and recurrence, making them critical therapeutic targets. This study investigated two isoeugenol-derived polyphenolic compounds, designated as 1 and 2, in breast, prostate, and colon CSCs using monolayer and three-dimensional tumoroid models. After 48 h, both compounds significantly inhibited proliferation. In prostate cancer cells, compound 2 exhibited a lower half-maximal inhibitory concentration (17.18 µM) than compound 1 (21.04 µM) and 5-fluorouracil (5-Fu) (21.51 µM). In three-dimensional tumoroids, compound 2 reduced tumoroid diameters by an additional 8% compared to 5-Fu. Molecular docking with AutoDock 4.2 revealed strong interactions between both compounds and key stemness regulators Sox2, Oct4, and Nanog. Compound 2 displayed the most favorable binding energies (-6.31 kcal/mol for Oct4, -5.36 for Nanog, and -4.62 for Sox2), suggesting stable complex formation that may disrupt core transcription factors. These findings support further investigation of polyphenol derivatives as potential CSC-targeting agents, with additional in vivo and pharmacokinetic studies needed to confirm therapeutic viability.
Insights
Two novel polyphenol compounds effectively inhibited cancer stem cell proliferation. Compound 2 showed superior efficacy, targeting key stemness regulators and offering potential for new cancer therapies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Cancer stem cells (CSCs) are crucial drivers of tumor initiation, metastasis, drug resistance, and recurrence.
- Targeting CSCs is a promising strategy for developing more effective cancer therapies.
Purpose of the Study:
- To investigate the anti-cancer stem cell effects of two isoeugenol-derived polyphenolic compounds.
- To evaluate the compounds' efficacy in breast, prostate, and colon cancer stem cells using in vitro models.
Main Methods:
- Utilized monolayer and three-dimensional tumoroid models to assess compound effects on CSCs.
- Determined half-maximal inhibitory concentrations (IC50) for compounds and 5-fluorouracil (5-Fu).
- Performed molecular docking simulations with AutoDock 4.2 to analyze interactions with stemness regulators (Sox2, Oct4, Nanog).
Main Results:
- Both compounds significantly inhibited CSC proliferation after 48 hours.
- Compound 2 demonstrated lower IC50 values in prostate cancer cells compared to compound 1 and 5-Fu.
- Compound 2 further reduced tumoroid diameters compared to 5-Fu and showed favorable binding energies with key stemness transcription factors.
Conclusions:
- Isoeugenol-derived polyphenolic compounds show significant potential as CSC-targeting agents.
- Compound 2 exhibits promising anti-CSC activity, warranting further investigation.
- Additional in vivo and pharmacokinetic studies are necessary to establish therapeutic viability.
