As ecologists keep telling us, you never know what plant or animal harbors a cure for a serious disease. Pancreatic cancer is about as serious as it gets. Each year, about 40,000 Americans are diagnosed with the disease, and only about 5% survive for five years after diagnosis. For a number of reasons – including difficulty detecting early signs and a lack of effective pancreatic cancer drugs – this survival rate has not changed for three decades (Jemal et al. 2010). There's hope, however, that this stalemate will soon end. In 2012, a University of Minnesota research team led by Drs. Rohit Chugh and Ashok Saluja reported that a compound derived from a Chinese medicinal herb called "Thunder God Vine” (Tripterygium wilfordii) effectively kills pancreatic cancer cells in several complimentary in vitro and in vivo models (Chugh et al. 2012). Follow-up clinical studies may finally give us the weapon we need to fight this dreaded cancer.
Saluja and his colleagues had shown that triptolide, the cancer-fighting agent in the Thunder God Vine, is highly effective against a number of cancer cell lines, including those derived from pancreatic and colon cancers, neuroblastoma and cholangiocarcinoma (Phillips et al. 2007; Antonoff et al. 2009; Clawson et al. 2010). However, triptolide's poor solubility in water limited its usefulness. Not to be deterred, Saluja and Chugh synthesized a water-soluble triptolide analog and called it Minnelide. They found that, like triptolide, Minnelide effectively kills pancreatic cancer cells in multiple complimentary models: pancreatic cancer cell lines, an orthotopic pancreatic cancer mouse model, a xenograft pancreatic cancer mouse model, and a spontaneous pancreatic cancer mouse model. Their key findings are summarized below:
- Minnelide significantly decreases the viability of five different pancreatic cell lines, whether derived from primary tumors, ascites or metastases.
- Minnelide either eliminates or significantly reduces the tumor burden in NU/J (002019) mice implanted orthotopically with pancreatic cancer cell lines, including two that are highly metastatic.
- In NU/J mice, Minnelide regresses tumors developed from an orthotopically implanted highly metastatic pancreatic cancer cell line.
- Minnelide regresses human pancreatic tumor xenografts in immunodeficient NOD.CB17-Prkdcscid/J (001303) mice, indicating that it is effective not only against cell lines but against more representative human-like tumors.
- Minnelide prevents tumors from forming in immunocompetent KrasG12D; Trp53R172H; Pdx-1Cre mice*, which normally die of spontaneously arising pancreatic cancer by the time they're five months old, indicating that it is effective in a natural tumor microenvironment that includes stroma and several immune cell types.
- Minnelide is effective at low doses and via multiple application methods.
- At the doses administered in this study, Minnelide is not toxic (tested in C57BL/6J (000664) mice).
In summary, the Chugh and Saluja team demonstrated that Minnelide, a water-soluble analog of triptolide, a cancer-fighting compound in the Chinese medicinal herb Thunder God Vine, can both prevent and regress pancreatic cancer in several complimentary in vitro and in vivo models in mice. In these models, Minnelide is more effective than gemcitabine, the leading chemotherapeutic used to fight human pancreatic cancer. It is effective at low doses, at different stages of cancer progression, can be administered via multiple methods, and is not toxic. After three decades, might there finally be a drug that can stop one of the deadliest cancers in its tracks? For the answer to this question, we'll have to wait on the outcomes of forthcoming clinical trials.
*These triple mutants are produced via a breeding scheme involving B6.129S4-Krastm4Tyj/J (008179), 129S-Trp53tm2Tyj/J (008652), and B6.FVB-Tg(Ipfl-cre)6Tuv/J (014647) mice.