Identification Of Triptolide, A Natural Compound, As An Inhibitor Of Hedgehog Signaling Pathway

Pancreatic cancer is the most dangerous of human malignancies and its 5-year survival rate is only 3%. First-line chemotherapy gemcitabine(GEM) alone or in combination with other drugs for locally advanced or metastatic pancreatic cancer can’t markedly improve the 5-year survival rate.Hedgehog signaling pathway (HH) is one of the crucial regulators of vertebrate embryonic patterning and development and is highly conserved in many species. Aberrant HH signaling pathway is involved in the initiation, development and metastasis in many human cancers. HH signaling pathway has become a valuable therapeutic target in multiple tumors including pancreatic cancer. We designed a series of experiments to screen natural small molecules to identify compounds that effectively inhibit activity of HH signal pathway. We found that triptolide (PG490) strongly inhibited HH pathway activation in concentration-dependent manner, and importantly, it overcame acquired resistance to smoothened mutation. Further study showed that triptolide couldn’t bind to smoothened and it may be act as a new GLI inhibitor. In vitro results indicated that triptolide strongly inhibit the growth of pancreatic cancer cells and induce apoptosis. In a tumor xenograft, combination of triptolide and chemotherapeutic drugs GEM significant inhibited the growth of pancreatic cancer. In summary, our results show that triptolide is a potent inhibitor of HH pathway and reveal a new mechanism for the anticancer activity of triptolide.