Podophyllotoxin Derivatives in Oncology: Mechanistic Insights, Therapeutic Applications, and Future Directions.

Podophyllotoxin (PTOX), a plant-derived aryltetralin lignan, has long been appreciated for its strong cytotoxic and antimitotic properties. Various derivatives of PTOX, including etoposide and teniposide, are well-established chemotherapeutics, although their use is largely hampered by systemic toxicity, low solubility, and drug resistance. Recent developments in modern chemistry and cancer biology have led to growing interest in developing novel PTOX-derived compounds with improved efficacy and reduced toxicity. This review presents the molecular mechanisms underlying the antitumor activity of PTOX and its derivatives, with particular emphasis on the inhibition of tubulin polymerization and DNA topoisomerase II. Furthermore, the roles of key signaling pathways, including PI3K/AKT, NF-κB, AMPK/HIF-1α, and Chk2/Twist1/EMT, in mediating antitumor effects in breast, lung, liver, and colorectal cancers are highlighted. Recent strategies involving the incorporation of PTOX into nanoparticles, hybrid molecules, and other bioactive systems have expanded its therapeutic potential by improving solubility, pharmacokinetics, and tumor selectivity. Overall, understanding structural modifications and molecular interactions of PTOX derivatives provides a strong foundation for the rational design of more potent and targeted anticancer agents.