Researchers at UT Southwestern Medical Center in Dallas have identified a compound that selectively eliminates cancer cells while sparing immune cells in a form of cell death known as ferroptosis, according to a news release. 

UTSW said the findings, published in Science Translational Medicine earlier this year, could lead to new treatments for a wide variety of cancer types.

“Our study is the first to report a cancer cell-specific induction of ferroptosis,” said Daolin Tang, M.D., Ph.D., professor of surgery at UT Southwestern, who co-led the study with Rui Kang, M.D., Ph.D., associate professor of surgery at UT Southwestern. Tang and Kang are members of the Harold C. Simmons Comprehensive Cancer Center.

Tang leads a research group that studies how our body’s cells signal for help when they’re damaged or stressed. Inflammation, the group notes, is a basic response to infection and injury in all living things with more than one cell.

UT Southwestern said that researchers elsewhere discovered ferroptosis, a type of cell death characterized by an accumulation of large amounts of iron and uncontrolled lipid peroxidation, a little more than a decade ago.

Because some forms of cancer develop resistance to chemotherapy drugs, finding ways to prompt ferroptosis quickly became the focus of significant cancer research, Tang said. UTSW said that most of those efforts focused on inhibiting an antioxidant enzyme called GPX4, a master repressor of ferroptosis.

Cancer-killing compound

Tang said, however, that GPX4-inhibiting compounds identified thus far not only induced ferroptosis in cancer cells but also in a variety of immune cell types — causing side effects in lab animals while also hindering the immune system’s natural anti-cancer response.

In searching for a compound that targets GPX4 only in cancer cells, Tang, Kang, and their colleagues screened more than 4,200 compounds from a pharmaceutical company’s drug library, dosing human pancreatic cancer cells growing in petri dishes.

UTSW said those experiments found that a compound called N6F11 not only reduced the amount of GPX4 present in cells, but also readily caused these cells to die from ferroptosis. Almost half of the cells were dead within 12 hours, UTSW said.

The researchers had similar results when they dosed other cancer cell types, including bladder, breast, and cervical, with N6F11, UTSW said.

More experiments showed that N6F11 binds to another protein called TRIM25, which regulates the amount of GPX4 and other proteins and is especially abundant in cancer cells, the school said. That binding prompts TRIM25 to tag GPX4 with ubiquitin, a protein that directs GPX4 to cellular garbage dumps where it’s degraded.

With GPX4 gone, cells die from ferroptosis.

More testing and aiming for a viable drug

Further testing on mouse models with pancreatic cancer showed N6F11 not only virtually stopped cancer progression, Tang said, but also it appeared to be nontoxic for healthy tissues or cells.

The immune-inhibiting side effects seen in previous research focused on inhibiting GPX4 were absent with N6F11.

In the next phase, UTSW said that researchers gave animals a combination of N6F11 and a cancer treatment known as an immune checkpoint inhibitor that is commonly used in patients. That combination improved their survival rates significantly compared to mice that received either treatment separately.

Tang said that future research will focus on developing N6F11 into a viable drug — a process that could take several years — as well as searching drugs already approved by the U.S. Food and Drug Administration for those that act similarly to N6F11, which would require less time and money.

Other UTSW researchers who contributed to this study are Zhuan Zhou, Ph.D., assistant professor of dermatology, and Chunhua Yu, M.D., Ph.D., manager of the Tang Lab.

This study was funded by National Institutes of Health grants.

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