Comprehensive Biotechnological Strategies for Podophyllotoxin Production from Plant and Microbial Sources.

Podophyllotoxin is derived from plant sources and exhibits strong anticancer activity. However, limited natural availability and environmental impacts from traditional extraction methods drive the search for alternative production approaches. This review explores diverse strategies for sustainable podophyllotoxin synthesis, including biosynthesis, semi-synthesis, and biotransformation. Biosynthetic methods involve metabolic pathway engineering in plant or microbial cells, enabling increased yields by manipulating precursor availability and gene expression. Semi-synthetic approaches modify podophyllotoxin precursors or intermediates to enhance therapeutic effects, with derivatives like etoposide and teniposide showing clinical efficacy. Biotransformation, utilizing organisms such as endophytic fungi or human hepatic enzymes, enables the transformation of substrates like deoxypodophyllotoxin into podophyllotoxin or its derivatives, yielding compounds with reduced environmental impact and improved purity. The anticancer efficacy of podophyllotoxin and its derivatives stems from multiple mechanisms. These compounds disrupt cell mitosis by inhibiting microtubule assembly, impairing nucleoside transport, and blocking topoisomerase II activity, leading to DNA cleavage and cancer cell apoptosis. Podophyllotoxin and its derivatives also exhibit anti-angiogenesis and anti-metastatic effects through signalling pathway modulation. Notably, derivatives like deoxypodophyllotoxin utilize advanced delivery systems, enhancing targeted efficacy and reducing side effects. Given the varied mechanisms and growing therapeutic applications, optimizing biotransformation and delivery techniques remains essential for advancing podophyllotoxin-based therapies. This comprehensive review underscores the compound's potential as a robust anticancer agent and the need for continued research to maximize its production and clinical effectiveness.