A combination of grape seed extract (GSE) and the grape compound resveratrol suppresses colon cancer stem cells with efficacy similar to that of a chemopreventive drug, but without the latter’s adverse effects, according to Pennsylvania State University researchers. They believe their findings could open the door to novel therapies to prevent colorectal cancer.
Public education and screening have contributed to a decades-long drop in the colorectal cancer death rate, according to the American Cancer Society. Nevertheless, CDC data show the disease remains the third most common cancer in men and women — ranking below prostate cancer and lung cancer in men, and breast cancer and lung cancer in women — and the second-leading cause of cancer death for both sexes, trailing only lung cancer, in the United States. Links between plant-rich diets and lower incidence of colorectal cancer are well-established in scientific literature, although precisely why fruits and vegetables seem to protect against the disease remains unclear. A Penn State study added to the growing body of evidence by using a combination of GSE and resveratrol — substances previously shown separately to have anti-cancer properties.
Stem Cells in the Crosshairs
The researchers chose to target colorectal cancer stem cells due to the outsize role they play in tumor development, according to Lavanya Reddivari, PhD, Assistant Professor and Research Associate at Penn State College of Agricultural Sciences and an author of the study.
“Colon cancer stem cells [are] a minor fraction compared to the total number of cancer cells, but these cancer stem cells are responsible for initiating tumor formation,” Reddivari says. “In addition, we know that these stem cells are resistant to certain cytotoxic factors of the drugs we normally use. They are difficult to eliminate with current therapy, but it’s essential for us to eliminate them to cure the cancer completely. Given the importance of these stem cells and their resistance to therapeutics, we thought they would be a good target.”
The researchers measured the efficacy of a GSE/resveratrol combination against that of sulindac, a nonsteroidal anti-inflammatory drug known to kill cancer stem cells. The team injected mice with a carcinogenic compound to induce colorectal cancer and divided them into three groups: One group received GSE and resveratrol mixed with food, another received sulindac and food, and the control group ate a normal diet.
In the mice that received the GSE/resveratrol diet, tumor formation decreased by 50 percent compared with the control group — a result proportional to the drop the researchers observed in the sulindac group. The GSE/resveratrol combination also induced apoptosis of cancer stem cells, reduced the number of intestinal crypts (glands) containing cancer stem cells and curbed the spread of cancer stem cells at levels consistent with those of sulindac. The in vitro results corroborated the team’s in vivo findings. The scientists were surprised not only by the similar levels of tumor suppression by GSE/resveratrol and sulindac, but also by the precision with which the grape compounds attacked the cancer stem cells.
“In the cell cultures and the animal models, the grape compounds were not targeting the normal stem cells,” says Jairam K.P. Vanamala, PhD, an author of the study, Associate Professor of Food Science at Penn State College of Agricultural Sciences, and faculty member of Penn State Hershey Cancer Institute and Penn State Center for Molecular Immunology and Infectious Disease. “Instead, they were going after the cancer stem cells. We were excited to see that selectivity of the natural compounds compared to sulindac.”
Vanamala and his colleagues will continue to investigate GSE and resveratrol to pinpoint their mechanisms of action. A key clue, he says, could be that when the researchers added an antioxidant to the cell culture, the effect of the grape compounds in promoting apoptosis of cancer stem cells disappeared. A researcher who was not involved with the study, Molly Millett, PhD, Clinical Evaluation Specialist at Colorado-based biotechnology company Terumo BCT, notes that GSE and resveratrol are composed of multiple compounds that can act against many of the proteins involved with the dysregulated pathways of cancer cells.
“Because of resveratrol/GSE’s ability to target multiple proteins, this prevents the cancer cells from becoming treatment-resistant,” Millett says. “Vanamala’s study demonstrated resveratrol/GSE’s ability to be efficacious with or without the p53 [tumor suppressor] protein. In addition, studies have been done examining the efficacy of individual compounds contained in GSE, and no single agent is as effective as GSE’s complex mixture. What remains is to study the effects of resveratrol/GSE within the human population, specifically for the prevention and treatment of colorectal cancer.”
Reddivari agrees, at least with regard to the prevention aspect.
“I can comfortably say [GSE and resveratrol] have promise as a cancer prevention strategy,” she says. “Our focus is mainly prevention. However, GSE and resveratrol maybe could be applied in cases of recurrence after patients have gone through chemotherapy.”