Amanita phalloides. Photo: Flickr, stanze.

Could a deadly mushroom help battle cancer?

University of British Columbia chemists are working to unleash the cancer fighting potential of Amanita phalloides — a particularly nasty poison shroom

By Silvia Moreno-Garcia

Infamous. That might be the best description for Amanita phalloides. The highly toxic mushroom has been feared for centuries, earning it a spot in mystery novels (the mushroom did it) and history books (Roman Emperor Claudius was supposedly poisoned with it). Despite its deadly history, Amanita phalloides remains the cause of 90 per cent of the world’s mushroom-related deaths.

This tricky fungus — it can be confused with the edible field mushroom or the straw mushroom — has fascinated David Perrin for 17 years. The University of British Columbia chemist hopes that the mushroom known as the ‘death cap’ could help save lives as a cancer-fighting drug.

Amanita phalloides is “probably the mushroom that gives all mushrooms a bad name,” says David Perrin.

The ingredient that makes death caps so toxic

Death caps have some curious properties. Chief among them is the ability of one of its toxins, α-amanitin, to inhibit transcription — the biochemical process of transferring the information in a DNA sequence to an RNA molecule.

“Transcription is needed for cell homeostasis as well as growth. When this toxin stops transcription, the cell can’t even maintain its own state and dies,” Perrin explains.

Basically, the α-amanitin in the mushroom stops critical cellular processes, cold. Which is good news when it comes to cancer cells. A recent study showed the toxin prevented cancer relapse in mice bearing tumor xenografts that are resistant to chemotherapy. A previous study showed success curing mice with pancreatic cancer.

Amanita phalloides has also been nicknamed the “destroying angel.” Illustration: Flickr, Biodiversity Heritage Library.

But scaling up is an issue — Amanita phalloides can’t yet be cultured on an artificial medium and yields are still low by fermentation. Researchers looking into the cancer-fighting potential of death caps have had to rely on mushrooms collected in the wild. Besides being time-consuming, only small amounts of the toxin can be extracted.

“You’d need kilos of mushrooms to extract enough α-amanitin to generate the amount needed to develop a treatment,” explains UBC PhD student Kaveh Matinkhoo, lead author on a paper describing the development of the first synthetic version of the toxin. “That’s a lot of bad mushrooms.”

This might not sound logical. After all, a single death cap is reputedly capable of killing a person. But ingesting a toxin is quite different from extracting it. Plus, you have to separate impurities from the mushroom along with other toxins (these additional toxins, in combination with α-amanitin, are the reason why a single death cap is, well, so deadly). Therefore, Perrin and his team have been determined to create a synthetic source of α-amanitin.

Left to right: Kaveh Matinkhoo, Alla Pryyma, David Perrin and Mihajlo Todorovic. Photo: Paul Joseph/UBC.

“The mushrooms are abundant in Eastern Europe, so you could envision people gathering them by the buckets, but the toxin wouldn’t be amenable to synthetic modification,” Perrin explained. “We don’t just put molecules on a shelf, what we’re making are derivatives.”

Synthesizing a toxin like α-amanitin is akin to a climbing a mountain — climbing it doesn’t help people, but mapping the route can be useful for everyone at the base. Similarly, mapping everything about the synthetic toxin can be useful when developing cancer therapies.

In the case of α-amanitin, besides being scalable — and you can imagine that a cancer drug would need to be available in large quantities — the synthetic toxin is useful because scientists can carefully manipulate its toxicity so that it doesn’t harm humans along with cancer cells.

The quest for synthetic amanitin lasted more than a decade. Photo: Paul Joseph/UBC.

Just like the real thing

Synthesizing α-amanitin, however, turns out to be quite the challenge. The biggest hurdle faced by UBC researchers was manufacturing 6-hydroxytryptathionine, one of the three building blocks of the toxin. The 6-hydroxytryptathionine molecule is so delicate it’s destroyed on contact with air.

“It looks so simple,” says Perrin. “If you show it to most synthetic chemists they’d say ‘There must be a way to get that.’ When you go to the literature, you find that no one has ever made it. And you start getting your head around this chemical and you think ‘I should be able to crank that out!’ But every permutation you try doesn’t work.”

Perrin and Matinkhoo were stuck. Then, in 2016 Perrin read a paper on oxidized tryptophan from a lab in San Diego. An atom of boron was involved in the oxidation step of the indole and he suspected this could be the solution to their problem. One of Perrin’s other students, Alla Pryyma, had experience working with fluorine. Perrin thought if Pryyma and Matinkhoo joined forces they could crack the α-amanitin puzzle.

Left: Alla Pryyma. Right: Kaveh Matinkhoo. Photo: Paul Joseph/ UBC.

“That’s this moment you have once in a while, which is so fun and exciting and full of trepidation, because you know you are going into uncharted territory. You’re like a kid saying ‘I just added one plus one and it equals two!’”

That is how the team developed a novel approach involving an atom of boron which produced the elusive 6-hydroxytryptathionine molecule, and finally a total synthesis of α-amanitin. In short, the synthetic toxin is identical to the natural one.

The next step, Perrin says, is to continue studying the toxin and developing antibody-drug conjugates, drugs that would utilize α-amanitin to kill cancer cells while sparing healthy ones. The benefit of α-amanitin is that it’s likely cancer cells would not become resistant.

Skin cancer cells. Photo: Flickr, ZEISS Microscopy.

“With some cancer therapies, they might supress the cancer, but it comes back. The way this toxin works, is that it kills rapidly growing cells, but also quiescent cells, which are dormant cells,” says Matinkhoo. “It increases the possibility of permanent treatment.”

The other benefit of α-amanitin is that patients wouldn’t likely require large doses or long courses of treatment. A couple of visits could suffice.

Synthetic α-amanitin is a first step toward a potential weapon in the battle against cancers, but an important step. And much like the death cap, drugs based on α-amanitin could pack quite a punch.

David Perrin’s lab at UBC. Photo: Paul Joseph/ UBC.

Learn more

“Synthesis of the Death-Cap Mushroom Toxin α-Amanitin” Journal of the American Chemical Society Article ASAP DOI: 10.1021/jacs.7b12698

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