Cruciferous Vegetables Studied for Prevention and Treatment of Pancreatic Cancer
Office of Cancer Complementary and Alternative Medicine
Division of Cancer Treatment and Diagnosis
Pancreatic cancer is one of the most aggressive and lethal solid tumor diseases. Four in five patients live for less than a year after diagnosis and less than five percent reach the five-year benchmark often used to assess cancer survival rates. Researchers are pursuing various approaches to address the urgent need for new and targeted therapeutics for pancreatic cancer.
Among the treatments that have shown early promise in pre-clinical studies is 3,3-diindolylmethane (DIM), a bioactive metabolic component of indole-3-carbinol (I3C) found in cruciferous vegetables like broccoli, Brussels sprouts, and cauliflower. Many cancer researchers studying this compound use a special formulation manufactured by BioResponse, Inc. called B-DIM. In several experiments, B-DIM has inhibited mTOR and Akt, two important molecular pathways in cell proliferation and invasion.
Fazlul Sarkar, Ph.D., professor of pathology at Wayne State University School of Medicine, is experimenting in cell cultures and with mice to demonstrate how B-DIM might effectively prevent as well as treat pancreatic cancer. “With many tumors, there is a switch that seems to unleash the cancer process,” he explained. The culprit in pancreatic cancer may be a recently discovered member of the platelet-derived growth factor (PDGF) family known as PDGF-D. “We find it prominently expressed in many of the tumors,” Dr. Sarkar added.
This NCI-supported research* is designed to study what happens to the development of pancreatic cancer cells when PDGF-D production is slowed (turned down) by B-DIM, focusing in particular on the impact on cancer stem-like cells. Cancer stem-like cells are the cells in pancreatic and other cancers that drive the reproduction and treatment resistance of cancer cells.
The first prominent effect on pancreatic cells in culture is interference with the expression of a gene called Notch-1, which has a role in cell growth. When Notch-1 is activated, so too is another of the main factors driving tumor progression and metastasis, NF-B, which could be reduced by B-DIM, Dr. Sarkar noted. In turn, two of NFB’s downstream gene targets are also impaired by B-DIM: MMP-9, a matrix metallopeptidase, which also helps cells to spread in the body and aids in bringing a new blood supply (angiogenesis) to the developing pancreatic tumor; and vascular endothelial growth factor, which also spurs angiogenesis, as well as other major steps in the cancer process.
All of these cancer-promoting factors are reduced when PDGF-D is turned down. “We’re confident of the results from B-DIM administration in cell culture,” said Dr. Sarkar, “because when we went the other way and turned up the PDGF-D production, all of these genes and carcinogenic effects increased.”
The next step, now underway, is to confirm that the same set of cellular processes actually happens in mice that are genetically altered to develop and mimic human pancreatic cancer. If that animal disease model proves responsive, Dr. Sarkar and his colleagues will test B-DIM as a way to turn down the PDGF-D production in the mice. The final step in this research strategy would be human clinical trials to test whether B-DIM could actually work as a non-toxic, dietary chemopreventive agent. “It may also be used in conjunction with conventional therapeutics to improve survival of patients diagnosed with this devastating disease,” he said.
NCI Program Director Isis Mikhail, M.D., M.P.H., Dr.P.H., commented, “I am very pleased with Dr. Sarkar’s progress on his innovative research project on B-DIM. The identification of novel therapeutics from this natural product fits well within OCCAM’s Research Development and Support Program portfolio. The findings have promising translational results for the prevention as well as treatment of pancreatic cancer, moving it from bench to bedside.”
*Grant Number: 1R01CA131151-02