From Pacific yew to pharmacy shelf: paclitaxel anti-cancer therapeutics — from discovery to clinical use
image: Figure 1. The paclitaxel biosynthesis pathway in Taxus. All enzymes present here have been charactered and verified; dashed arrows represent undefined catalytic sequences of enzymes.
Credit: Yu Haizheng, Lan Fen, Zhuang Yuan, Li Qizhang, Zhang Lianqing, Tian Hongchang, Bu Xiao, Chen Ruibing, Gao Yingying, Wang Zhuo, Zhang Lei
Nanjing, China — Paclitaxel, marketed as Taxol, is regarded as one of the most potent and commercially successful natural-product-derived anticancer agents. Since FDA approval in 1992 for advanced ovarian cancer, PTX and its derivatives have been approved for treating a broad range of malignancies, including breast, lung, cervical, and pancreatic cancers as well as Kaposi’s sarcoma. However, the bark of *Taxus* species contains PTX at only 0.01%–0.05% — insufficient to meet market demand — prompting researchers worldwide to explore alternative production methods and novel drug delivery systems.
The review first addresses the sourcing challenge. Beyond extraction from *Taxus* species, approximately 200 endophytic fungi have been found to biosynthesize PTX, while *Taxus* cell suspension cultures now yield powders containing approximately 40% PTX. Critically, the complete biosynthetic pathway of PTX — from geranylgeranyl diphosphate (GGPP) through the tetracyclic core baccatin III to final side-chain assembly — has only recently been established, enabling heterologous biosynthesis in engineered *E. coli* (taxadiene titer of ~1 g·L⁻¹, the highest reported to date), yeast (387 mg·L⁻¹ of taxanes), and *Nicotiana benthamiana*. The review also surveys chemical synthesis, from Potier’s four-step semisynthetic route from 10-DAB (underpinning the commercial process with 90% yield) to twelve landmark total syntheses tackling PTX’s highly oxygenated [6-8-6-4] core with 11 stereocenters.
Despite its clinical success, PTX’s physicochemical properties constrain its application: as a hydrophobic small molecule with extremely low water solubility, it requires a castor oil/ethanol vehicle that can induce hypersensitivity. To overcome these limitations, the review describes two parallel advances: PTX-releasing prodrugs, and a rich array of delivery systems — polymeric micelles (enhancing solubility by over three orders of magnitude), liposomes, BSA-based biological nanoparticles, and metallic nanoparticles such as gold and superparamagnetic iron oxide enabling chemo-photothermal combination therapy.
Mechanistically, PTX stabilizes microtubules and arrests cells at the G2/M phase. Beyond this classical mechanism, the review details recently elucidated cell-death pathways: ROS-mediated apoptosis (via JNK/caspase-3, PI3K/AKT/mTOR inhibition, and the p53–MEG3 axis), gasdermin-mediated pyroptosis, and RBFOX3–circ-IGF1R–mediated inhibition of NSCLC metastasis. Clinically, nab-PTX plus carboplatin is preferred for advanced TNBC, nab-PTX plus gemcitabine is standard for pancreatic cancer, and the KEYNOTE-407 regimen demonstrated a 5-year OS of 18.4% in NSCLC. A distinctive contribution is its treatment of PTX chemo-immunotherapy: beyond cytotoxicity, PTX enhances tumor immunogenicity by promoting dendritic cell maturation and inhibiting Tregs and MDSCs — a synergy confirmed by the Phase III trial of nab-PTX plus atezolizumab in metastatic TNBC.
In conclusion, PTX remains one of the most effective anti-cancer drugs developed in the past half-century. The recent biosynthetic pathway elucidation opens avenues for metabolic engineering and synthetic biology, and nanocarrier delivery systems have emerged as promising therapeutic options — establishing a robust foundation for developing novel natural anti-tumor agents to combat cancer in future therapeutic strategies.