Coumarin derivatives as anticancer agents targeting PI3K-AKT-mTOR pathway: a comprehensive literature review.

Abstract

Coumarin is a natural benzopyrone compound known for its diverse pharmacological activities, including anticancer, anti-inflammatory, and antioxidant properties. But its derivatives' exploration in cancer, specially PI3K-AKT-mTOR pathways-based cancer activity not explored yet. This review aims to evaluate the anticancer potential of coumarin derivatives' by exploring their modulatory effects on the PI3K-AKT-mTOR signaling pathway across diverse cancer types. This review adopted a systematic literature approach, emphasizing studies across various cancer types and focusing on coumarin's mechanisms and therapeutic potential. Results reveal that coumarin derivatives suppress PI3K-AKT-mTOR pathway activity across cancers, such as liver, breast, and colorectal, with IC₅₀ values ranging from 4 µM to > 200 µM in vitro and confirmed effects in vivo. The modulation of other pathways, including NF-κB and MAPK, underscores their multi-targeted anticancer action. Despite promising preclinical efficacy, challenges like low bioavailability, potential hepatotoxicity, and systemic toxicity persist. Structure-activity relationship (SAR) studies suggest that introducing specific functional groups can enhance selectivity, reduce toxicity, and improve therapeutic outcomes. The conclusion reinforces the potential of coumarin derivatives as novel anticancer agents, advocating for structural optimizations and clinical investigations to overcome pharmacokinetic barriers and maximize therapeutic benefits. This exploration offers a strategic perspective on utilizing coumarin-based molecules in advancing cancer therapeutics.