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Study Highlights Novel Approach to Promoting Cancer Cell Death

April 14, 2021

Jeffrey R. Peterson, PhD, author of the study and a professor in the Cancer Signaling and Epigenetics Program at Fox ChaseJeffrey R. Peterson, PhD, author of the study and a professor in the Cancer Signaling and Epigenetics Program at Fox Chase

PHILADELPHIA (April 14, 2021) – In a study published today, researchers at Fox Chase Cancer Center announced that they have discovered a novel approach to triggering a type of cancer cell death called ferroptosis that could have therapeutic potential.

Instead of targeting a cancer cell with a drug, the researchers attempted to harness the power of a nutrient—a naturally occurring fatty acid—to act as a type of Trojan horse that is taken up into the cancer cell, where it triggers cell death by ferroptosis.

“Ferroptosis was first characterized in 2012 and is still relatively new compared with the more commonly known type of cell death called apoptosis,” said Jeffrey R. Peterson, PhD, a professor in the Cancer Signaling and Epigenetics Program at Fox Chase. He conducted the study with lead author Alexander Beatty, PhD, a postdoctoral fellow in Peterson’s lab.

Breast cancer cells dying following eleostearic acid treatment. The green color shows the accumulation of toxic lipid peroxidation products in the cells.Breast cancer cells dying following eleostearic acid treatment. The green color shows the accumulation of toxic lipid peroxidation products in the cells.

“There is a lot of excitement around the possibility that ferroptosis can be harnessed to treat cancer. But the question is how,” Peterson added.

One of the hallmarks of ferroptosis is the accumulation of lipid-reactive oxygen species, toxic molecules that can accumulate and cause cell death. Peterson and colleagues conducted a study to explore whether ferroptosis in cancer cells could be triggered by using polyunsaturated fatty acids to form lipid-reactive oxygen species.

In their study, they were able to use alpha-eleostearic acid, a conjugated fatty acid, to induce ferroptosis in diverse cancer cell types. In a mouse model of triple-negative breast cancer, they orally administered tung oil, which is naturally rich in alpha-eleostearic acid, and found that it limited tumor growth and metastasis.

Additionally, Peterson and colleagues found that alpha-eleostearic acid did not alter the activity of glutathione peroxidase 4 (GPX4), a cellular enzyme that detoxifies lipid-reactive oxygen species. Other researchers have explored the use of GPX4 inhibitors that work to neutralize GPX4 and, thus, the cells’ ability to cope with those lipid-reactive oxygen species, causing their accumulation and leading to cell death.

“In principal, these two strategies can be combined therapeutically as two sides of the same coin,” Peterson said. “Inhibiting GPX4 and promoting lipid-reactive oxygen species would work together to drive cancer cell death.”

If drugs targeting GPX4 become available, these two strategies may be combined to enhance antitumor activity in patients.

The study, “Ferroptotic Cell Death Triggered by Conjugated Linolenic Acids is Mediated by ACSL1,” was published in Nature Communications.

The Hospital of Fox Chase Cancer Center and its affiliates (collectively “Fox Chase Cancer Center”), a member of the Temple University Health System, is one of the leading cancer research and treatment centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence five consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship and community outreach. It is the policy of Fox Chase Cancer Center that there shall be no exclusion from, or participation in, and no one denied the benefits of, the delivery of quality medical care on the basis of race, ethnicity, religion, sexual orientation, gender, gender identity/expression, disability, age, ancestry, color, national origin, physical ability, level of education, or source of payment.

 

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