Triptolide in Tripterygium wilfordii (Lei Gong Teng :雷公藤) is a Potent PAK Blocker

Triptolide, a diterpenoid triepoxide (MW: 360) from the traditional Chinese medicinal herb Tripterygium wilfordii (lei gong teng :雷公藤)  is a potential treatment for autoimmune and inflammatory diseases as well an anti-cancer and AD (Alzheimer’s disease) /PD (Parkinson’s disease) agent. It inhibits the growth of PAK1-dependent cancers such as pancreatic and colorectal cancer cells in vitro and in vivo.

In 2009, a Chinese group led by Qibing Mei at Xijing Hospital found (1) that Triptolide (0.3 mg/kg) decreased the incidence of tumors in nude mice inoculated with human colon cancer cell lines. Triptolide inhibited the proliferation, migration and colony formation of colon cancer cells (with the IC50 at around 30 nM).  Triptolide blocks the activation of  RAC, an activator of PAK1,  and eventually down-regulates cyclin D1 and CDK4 expression, leading to G1 arrest. Thus, like CAPE, Triptolide clearly inactivates PAK1. However, Triptolide causes a well-known side effect which reduces the sperm count in males. Thus, this herb extract is used as a male contraceptive as well. 

 

However, Triptolide is poorly soluble in water, limiting its clinical use. In 2012, Ashok Saluja’s group at University of Minnesota chemically synthesized its water-soluble analog (prodrug) called  ”Minnelide” (2).  The efficacy of Minnelide was tested both in vitro and in vivo models of pancreatic cancer, including an orthotopic model of pancreatic cancer using human pancreatic cancer cell lines in athymic nude mice. Minnelide was highly effective in reducing pancreatic tumor growth and spread, and improving survival. 

 

 Reference:

1. Wang Z, Jin H, Xu R, Mei Q, Fan D. Triptolide downregulates Rac1 and the JAK/STAT3 pathway and inhibits colitis-related colon cancer progression. Exp Mol Med. 2009; 41:717-27. 
2. R. Chugh, V. Sangwan, S. P. Patil, V. Dudeja, R. K. Dawra, S. Banerjee, R. J. Schumacher, B. R. Blazar, G. I. Georg, S. M. Vickers, A. K. Saluja, A Preclinical Evaluation of Minnelide as a Therapeutic Agent Against Pancreatic Cancer. Sci. Transl. Med. 4, 156ra139 (2012).