Pharmacological, computational, and mechanistic insights into triptolide's role in targeting drug-resistant cancers

As a promising candidate for tackling drug-resistant cancers, triptolide, a diterpenoid derived from the Chinese medicinal plant Tripterygium wilfordii, has been developed. This review summarizes potential antitumor activities, including the suppression of RNA polymerase II, the suppression of heat shock proteins (HSP70 and HSP90), and the blockade of NF-kB signalling. Triptolide is the first known compound to target cancer cells specifically but spare normal cells, and it has success in treating cancers that are difficult to treat, including pancreatic, breast, and lung cancers. It acts against the tolerance mechanisms, including efflux pump upregulation, epithelial-mesenchymal transition, and cancer stem cells. Triptolide modulates important cascades, including PI3K/AKT/mTOR, enhancing the efficacy of conventional therapies. Nonetheless, its clinical application is constrained by toxicity and bioavailability challenges. Emerging drug delivery systems, such as nanoparticles and micellar formulations, are being developed to address these limitations. It has strong interactions with key anticancer targets, like PARP, as determined in preclinical and computational studies consistent with its mechanism of action. Early-phase clinical trials of Minnelide, a water-soluble derivative of triptolide, are promising, but additional work is necessary to optimize dosing, delivery, and safety. This comprehensive analysis demonstrates that triptolide may constitute a repurposed precision medicine tool to overcome tolerance in cancer therapy.