A diagnosis of pancreatic cancer - the fourth most common cause of cancer death in the U.S. -can be devastating. Due in part to aggressive cell replication and tumor growth, pancreatic cancer progresses quickly and has a low five-year survival rate (less than 5 percent).
GRP78, a protein that protects cells from dying, is more abundant in cancer cells and tissue than in normal organs and is thought to play a role in helping pancreatic cancer cells survive and thrive. Researchers at the University of Minnesota have found triptolide, an extract of the Chinese herb thunder god vine (Tirpterygium wilforii), suppresses GRP78, eventually leading to pancreatic cancer cell death.
For mammals to use the proteins in our bodies, a process called protein folding must occur in the endoplasmic reticulum (ER) of cells. If proteins are not folded fast enough, unfolded proteins begin to build up and the cell becomes stressed. Prolonged ER stress activates a cellular process called the “unfolded protein response (UPR)”. Initially, the UPR helps kick-start the cell’s protein-folding ability, allowing it to function properly again. But if the problem doesn’t resolve, the UPR triggers cell death.
GRP78 helps cells survive long enough for the UPR to kick in and correct protein-folding problems. However, GRP78 is available in higher quantities in pancreatic cancer cells, which assists the cancer cells in evading cell death, allowing them to live and multiply.
Triptolide has previously been shown to have a negative effect on pancreatic cancer cell viability and to block growth and spread of these cells. In this study led by Ashok Saluja, Ph.D., researchers observed the effects of triptolide on human pancreatic cancer cells and tissue. They found that the UPR worked properly in triptolide-treated cells to allow cell death in malfunctioning cells.
Chinese herbal medicine has been used for the treatment of pancreatic cancer, especially for advanced cases. It is claimed to inhibit tumour growth and metastasis, improve pain and other symptoms, reduce the adverse effects of chemotherapy and/or radiotherapy, enhance immunity, prevent relapse, increase survival, and improve quality of life.
Twenty-four clinical trials (including 20 randomised clinical trials and 4 non-randomised studies) comparing Chinese herbal medicine alone or in combination with chemotherapy versus chemotherapy in advanced pancreatic cancer patients suggested beneficial effects on survival, quality of life, relief of chemo/radiotherapy side effects and improvement of symptoms. There is, however, a lack of methodological rigour in these studies, possible publication bias, and the potential benefit reported in the studies is not strong enough to support their use in the treatment of pancreatic cancer.
No adverse events of Chinese herbal medicines have been reported in the included clinical trials but reports of adverse events such as liver damage and kidney damage, and interactions between herbs and drugs are on record.
“Our study shows that although increased expression of GRP78 confers a survival advantage to the tumor cells, prolonged exposure to triptolide induces chronic ER stress, which eventually leads to cell death,” the authors stated. “In this context, inhibition of GRP78 by activation of the ER stress pathway by triptolide offers a novel mechanism for inhibiting the growth and survival of pancreatic cancer cells.”
The article “Triptolide activates unfolded protein response leading to chronic ER stress in pancreatic cancer cells” is published in the American Journal of Physiology - Gastrointestinal and Liver Physiology. It is highlighted as one of this month’s “best of the best” as part of the American Physiological Society’s APSselect program. View the full study here: ow.ly/yxpMq. Read all of this month’s selected research articles at apsselect.physiology.org/.
Herbal cure for pancreatic cancer
Successful laboratory-based experiments with the new molecule could open up a promising treatment avenue for pancreatic cancer patients, who have few options by way of therapies. The new drug has been developed from a plant chemical called triptolide found in a Chinese vine, Tripterygium wilfordii, that has a long history of use in Chinese medicine.
However, triptolide’s use as a new chemotherapeutic agent was hitherto limited because of a major bottleneck - the chemical’s poor solubility in water.
An 11-member team from the University of Minnesota, Minneapolis, has now developed a water-soluble version of the chemical and successfully tested its efficacy as an anti-cancer drug on cancer cell lines in the laboratory and mice. Seven out of 11 members of the team are of Indian descent.
The new drug from the modified compound - minnelide - named after Minnesota is tweaked for more effective delivery to pancreatic cells.
Minnelide was more effective in preclinical studies than gemcitabine, which was the first-line chemotherapeutic agent for pancreatic cancer, the researchers reported in October 17 issue of Science Translational Medicine. “It is highly efficacious in reducing pancreatic tumour growth and spread and improving survival. In one study, animals in the control group survived for 36 days, whereas animals treated with Minnelide continued to live for more than 385 days, more that 10-fold longer than untreated animals,” team leader Ashok Saluja told Deccan Herald.