A postive diagnosis of pancreatic cancer can be devastating. According to the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute, the number of new cases of pancreas cancer is expected to result in 12.3 per 100,000 men and women in 2014. The number of deaths is expected to reach 10.9 per 100,000 men and women per year. The lifetime Risk of Developing Cancer is approximately 1.5% of men and women will be diagnosed with pancreas cancer at some point during their lifetime. In 2013, there were an estimated 43,538 people living with pancreas cancer in the United States, making this cancer the fourth most common cause of cancer death in the United States.
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%).
…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…
Glucose-regulated protein 78 or 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 that triptolide – a diterpene tri-epoxide – an extract of tripterygium wilforii, a Chinese herb called or léi g?ng téng in Mandarin or thunder god vine in english, suppresses GRP78, eventually leading to pancreatic cancer cell death. Their study was published in the June 1, 2014 issue of the American Journal of Physiology—Gastrointestinal and Liver Physiology.
For proteins to be functioning in our bodies, a process called protein folding must occur in the endoplasmic reticulum (ER) of cells. If proteins are not folded fast or appropriately enough, unfolded proteins begin to build up and the cell becomes stressed.
A prolonged ER stress activates a cellular process called the unfolded protein response or 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, PhD., 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.
“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,” noted Nameeta Mujumdar, PhD, the lead author working at the Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota. “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.”
Triptolide is poorly soluble in water which limites its clinical use. Hence, in pre-clinical mouse studies, researchers evaluated a water-soluble prodrug of triptolide called Minnelide. In this unrelated and seperate study they found that the compound is well tolerated in animals, with no damage to normal cells. Minnelide is also undergoing clinical trials at the University of Minnesota. 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.
For more information:
 Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute. Cancer of the Pancreas. Fact Sheet. Last accessed July 1, 2014 [Fact Sheet]
 Mujumdar N, Banerjee S, Chen Z, Sangwan V, Chugh R, Dudeja V, Yamamoto M, Vickers SM, Saluja AK. Triptolide activates unfolded protein response leading to chronic ER stress in pancreatic cancer cells. Am J Physiol Gastrointest Liver Physiol. 2014 Jun 1;306(11):G1011-20. doi: 10.1152/ajpgi.00466.2013. Epub 2014 Apr 3.[Article][PubMed]
Photo: The extract of tripterygium wilforii, a Chinese herb called léi g?ng téng in Mandarin or thunder god vine in english, suppresses GRP78, eventually leading to pancreatic cancer cell death. In traditional medicine, this herb is also called thunder duke vine, and is used for treatment of fever, chills, edema and carbuncle.
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