Natural compounds against sarcoma: Which one shows the greatest potential?

Curcumin, berberine and other plant-derived compounds have long attracted scientific interest because of their anti-inflammatory and anticancer properties. A new study by researchers from Wroclaw Medical University and the University of Wroclaw, however, shows that not all natural compounds act in the same way, and strong anticancer activity does not always go hand in hand with a favorable safety profile.

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The researchers compared five compounds: curcumin, berberine, biochanin A, cucurbitacin E and CAPE (caffeic acid phenethyl ester), a component of propolis. They investigated how these substances affected fibrosarcoma cells and healthy muscle cells. The findings are published in the International Journal of Molecular Sciences.

A cellular control switch

The study focused on the NF-κB signaling pathway, which regulates inflammation, metabolism, cell survival and cellular aging.

"NF-κB acts like a central control switch that integrates cellular stress signals and determines whether a cell activates inflammatory pathways, fights for survival or changes its metabolism," said Julita Kulbacka, a professor in the Department of Molecular and Cellular Biology at Wroclaw Medical University.

In cancer cells, excessive activation of this pathway may promote survival and adaptation to adverse conditions. At the same time, NF-κB is essential for normal cell function, so the goal is not to switch it off completely but rather to modulate its activity as precisely as possible.

Cancer cells struggled more with energy depletion

The tested compounds disrupted mitochondrial function, reducing the cells' ability to produce energy.

In fibrosarcoma cells, ATP levels decreased by approximately 83–92%, compared with reductions of around 23–73% in healthy muscle cells. This suggests that cancer cells are more vulnerable to disturbances in energy metabolism.

The compounds also affected mitophagy, the process responsible for removing damaged mitochondria.

"Berberine, cucurbitacin E and CAPE enhanced PINK1/PARKIN-dependent mitophagy in fibrosarcoma cells. Combined with the marked reduction in ATP levels, this indicates not a protective response but an overwhelmed adaptive mechanism leading to cellular senescence and death," Kulbacka said.

Cancer cells stopped dividing

All five compounds induced features of cellular senescence in fibrosarcoma cells. In this state, cells remain alive but permanently lose their ability to divide.

The strongest effect was observed with curcumin. The proportion of senescent cancer cells increased from approximately 16.5% to more than 75%. For the other compounds, the percentage also exceeded 66%.

Healthy muscle cells generally showed a weaker response, suggesting a degree of selectivity toward cancer cells.

Curcumin showed the best overall balance

Cell viability experiments demonstrated that curcumin and CAPE exhibited the greatest selectivity against fibrosarcoma cells. Curcumin combined strong anticancer activity with induction of cellular senescence while maintaining a relatively favorable safety profile.

"Our findings show that these natural compounds can selectively place a greater metabolic burden on cancer cells than on healthy cells by disrupting mitochondrial function and energy metabolism. Among the compounds tested, curcumin demonstrated the most balanced profile," Kulbacka said.

Berberine was also well tolerated, although its effects on the mitochondria of healthy muscle cells require further investigation.

Effectiveness alone is not enough

To assess safety, the researchers also used greater wax moth (Galleria mellonella) larvae as an initial toxicity model.

Berberine and curcumin were the best-tolerated compounds. CAPE and cucurbitacin E caused higher mortality, while biochanin A proved to be the most toxic.

These findings demonstrate that strong anticancer activity alone is not sufficient for a compound to become a promising drug candidate. Safety for the whole organism is equally important.

This is not yet a treatment

The results do not mean that curcumin, berberine or any of the other tested compounds can already be used to treat sarcomas. The study was performed using animal cell lines and a simple invertebrate model.

"Our findings come from laboratory experiments and preliminary tests on wax moth larvae. The next step is to evaluate these compounds in more advanced in vivo models and to better understand their mechanisms of action, optimal dosing and delivery methods," Kulbacka said.

The study nevertheless identifies the compounds that deserve further investigation and highlights why the evaluation of natural anticancer agents should consider not only their effectiveness against cancer cells but also their effects on healthy tissues and the organism as a whole.

More information: Justyna Radzka et al, Modulation of NFκB Signaling by Natural Compounds in Sarcoma and Normal Muscle Models, International Journal of Molecular Sciences (2026). DOI: 10.3390/ijms27115025

Provided by Wroclaw Medical University