When oxidation can be beneficial

Contrary to popular belief, antioxidants aren’t a panacea. In fact, recent research in Science suggests that for controlling the growth of prostate cancer, prooxidants may be a better choice.

Back in 2008, a clinical trial testing antioxidant supplements in men with prostate cancer was ended early because the supplements were in fact harming the participants. Lloyd Trotman, who was starting his lab at Cold Spring Harbor at the time, recalls that researchers who had conducted the study “were quite devastated” by the results.

The study started a sea change in how researchers think about antioxidants, Trotman says. It later inspired him to investigate whether dietary prooxidants might be of use for controlling cancer cells. Now, in a paper in Science, Trotman and more than 40 coauthors report that dietary supplementation with a molecule called menadione sodium bisulfite, a precursor to vitamin K, can slow growth in a mouse model of prostate cancer (2024, DOI: 10.1126/science.adk9167).

After observing that their hunch about prooxidants slowing cancer cell growth was right, the researchers used single-cell sequencing to identify a few cancer cells in each mouse that could keep growing despite the treatment. This revealed that the prooxidant’s cancer-arresting effect depends on the lipid kinase VPS34.

VPS34 creates a phospholipid that marks the surface of endosomes—organelles formed when a cell gulps down new nutrients or recycles materials from its surface. But menadione bisulfite can oxidize reactive cysteines in VPS34 in cancer cells, blocking some of the enzyme’s activities. Without the phosphorylated lipid marker PI3P, cellular machinery cannot recognize early-stage endosomes and send them to the appropriate destinations. Instead, the researchers observed that the organelles swelled until they burst and killed the cells. “It’s completely unexpected that an oxidative stress could induce that lowering of the [PI]3P, which then immediately causes the cell death,” Trotman says.

Reactive cysteines are among the most-discussed cancer drug targets, says Alex Toker of Beth Israel Deaconess Medical Center, who studies a related lipid kinase family in cancer. He doubts that VPS34 is the only protein with cysteines vulnerable to oxidation by menadione sodium bisulfite. A key question, Toker says, is “How much of the activity of this molecule . . . is going to be down to the cysteine oxidation of this protein?”

Trotman also suspects that menadione sodium bisulfite oxidizes other molecules. But he says the study clearly demonstrates that VPS34 is important and is the first to show that it could potentially be druggable. “VPS34 was super cold from a cancer perspective,” before this, because endosomal trafficking is so important that a cell cannot survive without it, Trotman says. But this study suggests that VPS34 within cancer cells may be extra susceptible to oxidative stress—perhaps because cancer cells use most of their reducing potential to copy DNA and proliferate.

But this finding will need much more research before it can be extrapolated to people. There is no evidence that a menadione supplement would work in humans as it does in mice, and in the absence of cancer, there is evidence that excessive oxidation can be harmful. Whether human dietary modifications might exploit cancer cells’ apparent vulnerability to redox cell death remains to be proven—and after all, supplement studies have disappointed the field before.