Researchers find way to kill recurrent prostate cancer with high iron

Prostate cancer can come back from regular hormone withdrawal therapy with a vengeance and no clear treatment option, but scientists have early evidence that one way to kill these recurring cancer cells may be with plenty of iron.

The metal that is key to our red blood cells that carry oxygen and other body foundations is also known to be lethal to cells in large doses, but prostate cancer cells are essentially impervious to it, says Dr. Chunhong Yan, a molecular biologist at the Georgia Cancer Center. and Department of Biochemistry and Molecular Biology at the Medical College of Georgia.

Yan is putting together a strategy to change that and enable iron death for treatment-resistant prostate cancer through a process called ferroptosis. Despite its essence, high levels of iron also generate high levels of toxic free radicals, or ROS, whose effects include damaging lipids or fats, which are also essential for cell function.

“When the cell takes in iron, it goes through several processes that generate a lot of ROS,” said Yan, principal investigator of a new $1.1 million idea development award from the US Department of Defense.

While it is common for iron and ROS to interact, it damages lipids, an important part of cell membranes, when levels of both are high.

What we’re trying to do is take advantage of this side effect to treat prostate cancer

Chunhong Yan, Molecular Biologist, Georgia Cancer Center and Department of Biochemistry and Molecular Biology, Medical College of Georgia

Through this process called lipid peroxidation, lipids, which are also important energy reserves for cells and for internal cell signalling, aggregate and lose their flexibility and efficiency and eventually the cell dies, although exactly why remains a bit of a mystery.

Those lipid changes sound and are very destructive, but prostate cancer can be particularly refractory to them and to drugs designed to cause this kind of excess iron damage, because the cancer cells already need some similar changes in lipids in the cell membrane to make sure that they have the large amount of energy they need to survive, grow and propagate.

But the MCG research team has found that the gene, ATF3, a regulator of cell stress that they’ve shown can also suppress prostate cancer, may make prostate cancer cells more vulnerable to a newer compound, JKE-1674, which can help induce ferroptosis.

Basically, if you decrease the ability of prostate cancer cells to ignore stress, they will die, Yan says.

Another piece of the puzzle they’ve found is that the drug bortezomib, a chemotherapeutic agent used to treat multiple myeloma, a cancer of the plasma cells that normally produce antibodies to protect us from infection, is a good partner. because it increases the expression of ATF3, or activating transcription factor 3. ATF3, in turn, induces the expression of HMOX1, an enzyme and known antioxidant that actually releases iron from sites like hemoglobin, allowing more to build up in cells, which is lethal. is.

Another component is the body’s natural mechanism for dealing with this unhealthy combination of iron and ROS, so many good cells don’t die as a result. It is called glutathione peroxidase 4 or GPX4, which is an antioxidant and inhibitor of ferroptosis. One way JKE-1674 works is by inhibiting GPX4, which has the added benefit of repairing some of the damage to the lipids that make prostate cancer cells impervious to death from ferroptosis. These types of inhibitors have already shown promise in cancer treatment, Yan says.

Yan notes that clinical trials indicated that bortezomib is not particularly effective in treating prostate cancer, but when combined with JKE-1674, they have lab data that it becomes a potent enemy against the common cancer.

In a cell culture, Yan’s team saw how increased ATF3 expression sensitized human prostate cancer cells to death from iron, and the new DOD-funded studies allow for the following steps: to study the induction in a mouse with human prostate cancer, a humanized mouse model, to see whether ATF3-induced bortezomib in combination with JKE-1674 re-induces ferroptosis in advanced, usually fatal, prostate cancer.

They also have a new genetically engineered mouse that also generates more ATF3 and will see if that also makes prostate cancer more vulnerable to ferroptosis.

Yan and his colleagues also want to learn more about how ATF3 makes prostate cancer cells more vulnerable to iron death using agents like bortezomib.

Yan’s lab uses existing drugs and drug regimens to efficiently identify a therapy that could move relatively quickly from his lab to clinical trial for the most common cancer in American men except non-melanoma skin cancer, and the second leading cause of death. by cancer, behind lung cancer, according to the American Cancer Society.

For example, patients receive an injection of bortezomib for multiple myeloma, and Yan is sticking to that schedule for his studies to try to ensure the translatability of the lab work to humans and thus, if they continue to find success, a rapid transition to a clinical trial.

There are currently several treatments for hormone-driven androgen-driven prostate cancer, and many therapies aim to reduce male hormones, such as testosterone, and/or prevent them from directly feeding prostate cancer, including surgical castration to remove the testicles. . , which produce most of the androgens, and which give drugs that bind to the androgen receptors so that the hormones cannot be active.

While these therapies are usually effective in the beginning, some cancers usually become treatment-resistant within 18-24 months, Yan says, drastically limiting available options, including a significant number of prostate cancers that become resistant to even newer drugs, such as the hormone therapy enzalutamide.

“That’s why it’s very important to find a therapy to treat this group of patients,” Yan says.

Ferroptosis was first described as a distinct form of cell death in 2012.

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