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 good safety profile.
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 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, - explains Prof. Julita Kulbacka from 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.
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, - says Prof. Julita Kulbacka.
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 exceeded 66% as well.
Healthy muscle cells generally showed a weaker response, suggesting a degree of selectivity towards cancer cells.
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, - emphasizes Prof. Julita Kulbacka.
Berberine was also well tolerated, although its effects on the mitochondria of healthy muscle cells require further investigation.
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.
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 in 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, - notes Prof. Kulbacka.
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.
Did you know?
Sarcomas account for less than 1% of all cancers in adults but include more than 100 different disease subtypes.
There is no single treatment that works for all sarcomas. Different subtypes often require different therapeutic approaches.
Cancer cells consume much more energy than most healthy cells.
When their “power plants”—the mitochondria—stop functioning properly, their ability to grow and divide is impaired.
Natural compounds may inspire the development of future medicines, but they are not therapies on their own.
International Journal of Molecular Sciences
Experimental study
Cells
Modulation of NFκB Signaling by Natural Compounds in Sarcoma and Normal Muscle Models
2-Jun-2026