From Signaling Pathways to Combination Therapy: Bioactive Compounds against Cancer Stem Cells.

Cancer Stem Cells (CSCs) represent a heterogeneous group of tumor cells that possess the innate ability to self-renew and differentiate, which also contributes to their resistance to first-line therapies. What sets CSCs apart from others is their crucial role in the recurrence of cancer, metastasis, and varied clinical responses against anti-cancer drugs, which makes them challenging to target. In recent years, there has been growing evidence that therapies capable of eliminating CSC niches or specifically targeting their core survival mechanisms are a potential means of providing a sustainable, long-term response to therapy and increasing disease-free survival rates. Bioactive compounds from natural sources have gained immense interest for their bio-efficacy, low toxicity profiles, and wide therapeutic index (TI), especially with their broad-spectrum ability of targeting multiple pathways while having little or no systemic side effects. Bioactive compounds can target major signaling pathways (Wnt/β-catenin, Notch, Hippo-YAP/TAZ, Hedgehog, PI3K/Akt/mTOR, NF-κB) to induce apoptosis, inhibit epithelial-mesenchymal transition (EMT), disrupt cancer stem cell niches, and other effects that suggest they resensitize to chemotherapeutic agents. Plant-derived biologics may be used as unique strategies targeting CSCs or as adjuncts reconstituted with custom conventional treatment plans, to mitigate drug resistance with mechanisms that involve targeting CSC metabolism, blocking protective autophagy, and the epigenetic landscape. The use of nanotechnology for targeted delivery of bioactive compounds is anticipated to provide better stability, bioavailability, and tumor accumulation. In this review, we outline a range of approaches using bioactive compounds for the eradication of CSCs, focusing on the mechanisms by which they work, the preclinical and clinical evidence supporting them, and their role in combination therapy approaches. This review also gives a comprehensive understanding of various other strategies and latest advancements that do not directly target the CSCs, including differentiation therapy, metabolic targeting, and immunomodulation, which, when used in conjunction with bioactive compounds, may resensitize the drug-resistant CSC population. We also discuss the therapeutic and translational potential of bioactive compounds and the future possibilities of combination, multi-targeted, CSC-based treatment strategies to eliminate tumor recurrences and improve cancer outcomes for patients.