Researchers dream of getting squash roots to make anti-cancer medicine

Green Innovation 12. feb 2023 2 min Professor Søren Bak Written by Kristian Sjøgren

The roots from Cucurbita pepo contain very promising substances that may hold great potential in fighting cancer – if you can get the plants to make enough.

Many people have not heard of cucurbitacins, but in cancer research, these biological substances derived from the Cucurbitaceae family of plants have attracted considerable interest. Cucurbitacins can stop cells from dividing, and stopping cancer cells from dividing can practically cure people with cancer.

Cucurbitacins taste bitter, and these have been removed from cucumbers (also in the Cucurbitaceae family) through plant breeding.

Wouldn’t it be nice if we could just harvest many squash and pumpkins to obtain huge quantities of potent cancer medicine? It is not that simple, as the researchers discovered.

Obtaining meaningful quantities of cucurbitacins from squash requires purifying tonnes of them, and this is not viable regarding rational production and sustainability.

Another method is to get the plants to overproduce cucurbitacins, and researchers came very close to accomplishing this.

In a recently published study, the researchers showed that they can get the roots from Cucurbita pepo to produce the exact cucurbitacins the researchers and oncologists want, but unfortunately not in quantities that make this type of production attractive.

“We want to produce large quantities of four or five cucurbitacins because they are so promising in cancer treatment but very difficult to obtain. These substances are also unbelievably expensive, and we got the plants to make the most promising cucurbitacins. Unfortunately, we also found that increasing the production of cucurbitacins in the roots becomes toxic to the roots themselves,” explains a researcher involved in the study, Søren Bak, Professor, Department of Plant and Environmental Sciences, University of Copenhagen.

The research has been published in Frontiers in Plant Science.

Bacteria stimulate the roots to grow

The researchers tried to get roots from Cucurbita pepo to make large quantities of cucurbitacins.

These hairy roots are interesting because bacteria can make the roots grow independently of the rest of the plant.

When infected with a certain type of bacteria, the roots from some plants begin to grow independently, and researchers can therefore grow large quantities of roots in the laboratory without needing sunlight or soil to grow them in. They just have to be exposed to water and nutrients once in a while.

This also means that the roots can eventually be grown in large tanks and then the cucurbitacins can be harvested.

“The bacteria have been doing this to plant roots for millions of years, and we mimic this to make large quantities of biomass to scale up production,” says Søren Bak.

Genetic engineering produced the right cucurbitacins

The researchers then genetically engineered the roots so that they produced only the cucurbitacins the researchers or doctors wanted.

This part of the research also succeeded, although the researchers do not yet thoroughly understand the signalling pathways the hairy roots use to make the various cucurbitacins.

“This is a proof of concept for now. We can make large quantities of hairy roots and can get them to make the exact cucurbitacins that are promising pharmaceutically,” explains Søren Bak.

Stumbling at the finish line

Nevertheless, the researchers stumbled at the finish line in the quantity of cucurbitacins they could get the roots to produce.

No matter how much they stimulated the plant roots, they could not get them to produce significantly more of the cucurbitacins.

The research clearly showed that cucurbitacins inhibit the growth of cells and can therefore be toxic to cancer cells and are also toxic in excessive quantities to the hairy roots themselves.

Søren Bak therefore concludes that both the hairy roots and the researchers have probably hit a biological maximum.

“We showed that we can make hairy roots from Cucurbita pepo roots, that we can change the production of cucurbitacins and that we can change how these cucurbitacins look. We did not succeed in making large quantities of cucurbitacins. The hairy roots cannot do this,” says Søren Bak.

Making cucurbitacins in yeast cells?

Although the research did not turn out to be the exciting breakthrough the researchers had hoped for, Søren Bak still thinks that there are other possibilities for mass-producing cucurbitacins not necessarily involving these hairy roots.

“We could eventually transfer the cucurbitacin synthesis pathway from the plants to yeast cells, for example, and thereby get them to make these valuable compounds. However, this requires identifying all the genes for the cucurbitacins. The advantage of hairy roots was that you did not need to know all the genes in the biosynthesis pathway. Likewise, we should probably expect that the cucurbitacins are toxic to yeast cells, and we must solve this,” concludes Søren Bak.

Metabolic engineering of cucurbitacins in Cucurbita pepo hairy roots” has been published in Frontiers in Plant Science. Søren Bak, Aldo Almeida and Sotirios C. Kampranis received support from Independent Research Fund Denmark and Søren Bak from a Distinguished Investigator grant under the Research Leader Programme of the Novo Nordisk Foundation for the project EcoSap: Triterpenoid Saponins as Green Solutions for Future Sustainable Food Production.

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