Grape seed extract halts cell cycle, checking growth of colorectal tumors in mice

October 18, 2006

PHILADELPHIA − Chemicals found in grape seeds significantly inhibited growth of colorectal tumors in both cell cultures and in mice, according to researchers who have already demonstrated the extract's anti-cancer effects in other tumor types.

Their study, published in the October 18 issue of Clinical Cancer Research, documented a 44 percent reduction of advanced colorectal tumors in the animals, and also revealed, for the first time, the molecular mechanism by which grape seed extract works to inhibit cancer growth. The authors found that it increases availability of a critical protein, Cip1/p21, in tumors that effectively freezes the cell cycle, and often pushes a cancer cell to self destruct.

"With these results, we are not suggesting that people run out and buy and use grape seed extract. That could be dangerous since so little is known about doses and side effects," said Rajesh Agarwal, Ph.D., professor in the Department of Pharmaceutical Sciences at the University of Colorado Health Sciences Center in Denver.

"The value of this preclinical study is that it shows grape seed extract can attack cancer, and how it works, but much more investigation will be needed before these chemicals can be tested as a human cancer treatment and preventive," he said.

The skin and seeds of grapes are a rich source of proanthocyanidins, a class of antioxidant flavonoids that remove harmful free oxygen radicals from cells. Grape products (juice and red wine) are known for their heart healthy effects, especially in lowering levels of blood cholesterol, Agarwal said, and because grape seeds contain higher concentrations of these chemicals, they are widely marketed as a dietary supplement.

Agarwal and his team of investigators were first to report, in 1999, that grape seed extract also has chemopreventive activity against skin cancer. Their subsequent preclinical work has shown that the extract also retards growth of prostate cancer cells.

In this study, Agarwal tested the extract on colorectal cancer, the second most common malignancy in Americans as well as the second leading cause of cancer deaths in this country. They exposed two different human colon carcinoma cells to the extract, and found a dose- and time-dependent inhibition of cell growth.

"Beneficial effects were correlated with how much extract was used and how long it was used for," Agarwal said. The number of live cells decreased by 92 percent in one cell line when the highest dose was given for the longest time period, which was two days, he said.

The researchers then performed a cell cycle distribution analysis, looking to see specific growth inhibitory effects. They found that the longer the extract was used, the more cells were "arrested" in the G1 phase of the cell cycle, the time when the cell is preparing to duplicates its DNA before dividing, and, correspondingly fewer cells had advanced to the "S" phase, when DNA is being actively duplicated.

They then studied the extract's effect on the molecular regulators that control the cell cycle, and found a strong dose-dependent increase in Cip1/p21 protein. In fact, the amount of Cip1/p21 protein within the cells increased by more than 150 times after 12 hours of treatment, Agarwal said. The researchers also noted a corresponding decrease in a number of different cyclin proteins and associated cyclin-dependent kinases (CDKs).

This all makes sense, according to Agarwal. One of the hallmarks of cancer is rampant cell growth due to loss of control of the cell cycle, and CDKs help push the cycle from a quiet state through to cell division. The Cip1/p21 protein, however, is powerful enough to inhibit the activity of CDKs and can also control apoptosis, or programmed cell death, he said.

"This protein physically interacts with CDKs," Agarwal said. "In normal cells, it attaches to CDKs to inhibit growth, but if a cell wants to grow, as it does in cancer, levels of Cip1/p21 are reduced, or non-functional."

Indeed, further experimentation demonstrated that grape seed extract increased the level of Cip1/p21 protein, allowing it to bind to and shut down the CDKs driving the cell cycle. The investigators also found that the extract can do that even if a cancer cell is missing p53 function (which also helps controls the cell cycle).

"That is good news, because most cancers are missing p53," Agarwal said.

Finally, the researchers tested the extract in mice. They implanted the animals with advanced human colorectal cancer cells and at the same time, gave the mice grape seed extract through a feeding tube. They tested only one dose, which was larger than a human would comparatively use, Agarwal said, and after eight weeks, tumor volume in treated mice were reduced by 44 percent and tumor weight by percent, compared to control animals. No toxic side effects were observed in treated mice, despite the high doses.

Similar to the cell culture studies, Cip1/p21 protein levels increased in tumors in mice treated with grape seed extract, Agarwal said.

As a first step toward translating their findings into the clinic, the research team now plans to determine the lowest effective, as well as the highest non-toxic doses, by which grape seed extract can offer anticancer benefit in mice.
-end-
The study was funded by grants from the National Cancer Institute.

Editors Note: For a PDF of this study, please e-mail decicco@aacr.org or Ortiz@aacr.org

The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, AACR is the world's oldest and largest professional organization dedicated to advancing cancer research. The membership includes more than 24,000 basic, translational, and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and more than 80 other countries. AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants.

The AACR Annual Meeting attracts over 17,000 participants who share the latest discoveries and developments in the field. Special Conferences throughout the year present novel data across a wide variety of topics in cancer research, diagnosis and treatment. AACR publishes five major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. Its most recent publication, CR, is a magazine for cancer survivors, patient advocates, their families, physicians, and scientists. It provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship and advocacy.

American Association for Cancer Research

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.