Natural-product polypharmacology in acute lymphoblastic leukemia: a state-of-the-art review

High-risk and relapsed/refractory (R/R) acute lymphoblastic leukemia poses significant therapeutic challenges due to emergent drug resistance and dose-limiting toxicities. Natural products, with their diverse chemical structures and pharmacological activities, provide a promising avenue for multi-target therapies.

This review analyzes key natural product classes, such as phenolic compounds, terpenoids, flavonoids, and alkaloids. It aims to elucidate their mechanisms by modulating critical oncogenic pathways to overcome drug resistance, paving the way for rational therapeutic design strategies.

A comprehensive literature review was conducted by systematically searching Web of Science, PubMed, and Google Scholar. Search queries combined "acute lymphoblastic leukemia" with various natural product classes, focusing on publications from 2000 to 2025. The analysis synthesized data on molecular mechanisms, pharmacokinetics, safety, and synergistic strategies for combination therapy.

The database search yielded 303,464 hits, with 13,839 hits from Web of Science, 14,625 hits from PubMed, and 275,000 hits from Google Scholar. After removal of duplicates, commentary articles, clearly ineligible literature, and records not within the predefined topic range were removed, 280 records were screened. 73 publications were assessed for eligibility, and 53 studies were included in the final synthesis. The studies considered in this review largely focused on chemically characterized natural products and derivatives comprising phenolic compounds, terpenoids, flavonoids, alkaloids, and artemisinin-related compounds. Most evidence was collected from preclinical ALL models and involved modulation of apoptosis, oxidative stress, cell-cycle arrest, autophagy, ferroptosis, and ALL-related signaling pathways. In conclusion, these natural products showed multi-target and pathway-intersecting activities that could improve conventional anti-leukemic treatment and overcome chemoresistance, although clinical translation remains limited by insufficient in vivo validation, insufficient PK/PD characterization, poor bioavailability, and incomplete safety evaluation.

Natural products offer a valuable resource for developing novel anti-ALL therapeutics. Their multi-target capability fosters synergistic combinations to combat resistance, highlighting the need for advanced technologies and precision medicine approaches in ALL treatment.