Article

Targeting Cancer Stem Cells with Phytochemicals: Molecular Mechanisms and Therapeutic Potential

Ashok Kumar SahDepartment of Medical Laboratory Sciences, College of Applied and Health Sciences, A’ Sharqiyah University, Ibra 400, OmanJoy DasSchool of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, Punjab, IndiaAbdulkhakov Ikhtiyor UmarovichDepartment of Faculty and Hospital Therapy, Bukhara State Medical Institute, Bukhara 200100, UzbekistanShwetha AgarwalSchool of Allied Health Sciences, Galgotias University, Greater Noida 203201, Uttar Pradesh, IndiaPranav Kumar PrabhakarDepartment of Biotechnology, School of Engineering and Technology, Nagaland University, Meriema, Kohima 797004, Nagaland, IndiaAnkur VashishthaDepartment of Medical Laboratory Technology, School of Allied Health Sciences, Sharda University, Greater Noida 201310, Uttar Pradesh, IndiaRabab H. EilshaikhDepartment of Medical Laboratory Sciences, College of Applied and Health Sciences, A’ Sharqiyah University, Ibra 400, OmanRanjay Kumar ChoudharyDepartment of Medical Laboratory Sciences, College of Applied and Health Sciences, A’ Sharqiyah University, Ibra 400, OmanAyman Hussein AlfeelMedical Laboratory Sciences Department, College of Health and Applied Sciences, Gulf Medical University, Ajman 4184, United Arab Emirates

Biomedicinesjournal2026en

ABI

Abstract

Cancer stem cells (CSCs) represent a small but highly resilient tumor subpopulation responsible for sustained growth, metastasis, therapeutic resistance, and recurrence. Their survival is supported by aberrant activation of developmental and inflammatory pathways, including Wnt/β-catenin, Notch, Hedgehog, PI3K/Akt/mTOR, STAT3, and NF-κB, as well as epithelial–mesenchymal transition (EMT) programs and niche-driven cues. Increasing evidence shows that phytochemicals, naturally occurring bioactive compounds from medicinal plants, can disrupt these networks through multi-targeted mechanisms. This review synthesizes current findings on prominent phytochemicals such as curcumin, sulforaphane, resveratrol, EGCG, genistein, quercetin, parthenolide, berberine, and withaferin A. Collectively, these compounds suppress CSC self-renewal, reduce sphere-forming capacity, diminish ALDH+ and CD44+/CD24− fractions, reverse EMT features, and interfere with key transcriptional regulators that maintain stemness. Many phytochemicals also sensitize CSCs to chemotherapeutic agents by downregulating drug-efflux transporters (e.g., ABCB1, ABCG2) and lowering survival thresholds, resulting in enhanced apoptosis and reduced tumor-initiating potential. This review further highlights the translational challenges associated with poor solubility, rapid metabolism, and limited bioavailability of free phytochemicals. Emerging nanotechnology-based delivery systems, including polymeric nanoparticles, lipid carriers, hybrid nanocapsules, and ligand-targeted formulations, show promise in improving stability, tumor accumulation, and CSC-specific targeting. These nanoformulations consistently enhance intracellular uptake and amplify anti-CSC effects in preclinical models. Overall, the consolidated evidence supports phytochemicals as potent modulators of CSC biology and underscores the need for optimized delivery strategies and evidence-based combination regimens to achieve meaningful clinical benefit.

Topics

Cancer Cells and Metastasis Curcumin's Biomedical Applications Mesenchymal stem cell research

Identifiers

DOI: 10.3390/biomedicines14010215

Citations and references

Cited by 0223 references

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