Antitumor mechanisms and future clinical applications of the natural product triptolide

Abstract

Triptolide (TPL) is a compound sourced from Tripterygium wilfordii Hook. F., a traditional Chinese medicinal herb recognized for its impressive anti-inflammatory, anti-angiogenic, immunosuppressive, and antitumor qualities. Notwithstanding its favorable attributes, the precise mechanism through which TPL influences tumor cells remains enigmatic. Its toxicity and limited water solubility significantly impede the clinical application of TPL. We offer a comprehensive overview of recent research endeavors aimed at unraveling the antitumor mechanism of TPL in this review. Additionally, we briefly discuss current strategies to effectively manage the challenges associated with TPL in future clinical applications. By compiling this information, we aim to enhance the understanding of the underlying mechanisms involved in TPL and identify potential avenues for further advancement in antitumor therapy.

Keywords: Clinical application; Molecular mechanism; Natural product; Triptolide; Tumor.

Fig. 1

Main signaling pathways involved in TPL in cancer. (A)TPL dampens the activation of the STAT3 signaling pathway by preventing STAT3 from binding to DNA. Simultaneously, it disrupts the binding interaction between Beclin1 and Mcl-1, resulting in decreased expression of genes controlled by STAT3, which are associated with anti-apoptotic, proliferative, and angiogenic functions. (B)TPL effectively inhibits NF-κB activity and reduces the protein expression of its subunits, c-Rel and Rel-A. Simultaneously, TPL binds to and activates p38α and ERK1/2, stabilizes p53, and inhibits IκBα phosphorylation. (C)TPL hinders the Wnt/β-catenin signaling pathway through the suppression of LRP6 phosphorylation, subsequently inhibiting DSH activation. This action leads to heightened expression of CDH1, WIF1, and other related factors. Additionally, TPL induces demethylation to provide further inhibition of the Wnt signaling pathway. (D)TPL enhances TRAIL-related signaling activation by increasing DR5 expression and reducing PUM1 expression, rendering cells more sensitive to apoptosis. It leads to an increase in p27 and CDK2 complexes, inducing autophagy. When combined with TRAIL, TPL causes lysosome-dependent cell death

Fig. 2

TPL induces cell death. TPL generates multiple modes of cell death, such as apoptosis, autophagy, pyroptosis and ferroptosis. The primary targets have been outlined in the figure

Fig. 3

The relevant toxicities associated with TPL. TPL can induce various toxicities, and the figure briefly summarizes the toxicological mechanisms underlying the hepatotoxicity, nephrotoxicity, and reproductive toxicity caused by TPL exposure

Fig. 4

A study of standard forms of application of TPL. (A) TPL in combination with other drugs. (B) TPL binding to modified nanoparticles. (C) TPL-conjugated antibodies enable targeted co-delivery. (D) TPL binding to liposomes and exosomes