Multi-Target Biological Activities of Podophyllotoxin-Derived Natural Products

Podophyllotoxin is a well-studied natural product. Because of its unique structure and ability to inhibit cancer cells, it has been changed in different ways to find out its pharmacological properties. This paper discusses the common chemical modifications of podophyllotoxin molecules, including the C-4 and E-4 site replacements. Furthermore, its common inhibitory effects on cancer cells and antiparasitic activities, among others, are outlined by the connection between conformational changes and pharmacological activities. Importantly, Podophyllotoxin can effectively overcome the phenomenon of multidrug resistance through a dual-targeting mechanism, including inhibition of microtubule protein synthesis and topoisomerase II activity, and induces cell cycle arrest and apoptosis. Recent findings reveal its potential to modulate immune responses through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, further extending beyond its classical mechanisms. This study finally provides a systematic summary of the activity of podophyllotoxin in common cancer cells, including those in the breast, lung, and prostate.