Cancer cells have the capacity to multiply rapidly. The aggressive cancer cells undergo conversion from their tightly connected epithelial state into a mesenchymal state, which lacks contact restrictions and spreads easily to other parts of the body. Such epithelial-to-mesenchymal plasticity also makes the cancer cells resistant to elimination by anticancer therapies.
The search is ongoing for newer anticancer agents that can overcome this acquired resistance to therapy and destroy the 'rogue' cancer cells. A group of researchers led by Dr. Hideyuki Saya, Director of the Oncology Innovation Center, Fujita Health University, Japan, has uncovered the mechanism of the anticancer activity of benzaldehyde, a compound responsible for the aroma of almonds, apricots, and figs.
Giving insights into their motivation for this study, Dr. Saya explains, "In the 1980s, researchers demonstrated the anticancer activity of benzaldehyde and its derivatives. The first author of our study, Dr. Jun Saito, is the daughter of one of the researchers involved in those early studies, and she was driven by a strong desire to uncover the mechanism behind benzaldehyde's anticancer effects." This study, published online in the British Journal of Cancer on May 02, 2025, shows the impact of benzaldehyde on key signaling protein interactions within the cancer cells and the resulting cytotoxicity.
Early studies reported the ability of benzaldehyde to inhibit the progressive development of mouse embryonic cells, indicating its potential in preventing rapid cell proliferation. Here, the anticancer effects of benzaldehyde were studied by using a mouse model grafted to have a growing pancreatic cancer.
In cell culture studies, benzaldehyde inhibited the growth of cancer cells resistant to radiation therapy and also those resistant to treatment with osimertinib, an agent blocking tyrosine kinases in growth factor signaling. Benzaldehyde synergized with radiation to eliminate previously radiation-resistant cancer cells.
The study findings revealed that benzaldehyde exerted its anticancer effects by preventing interactions of the signaling protein 14-3-3ζ with the Ser28-phosphorylated form of histone H3 (H3S28ph). This interaction, key to cancer cell survival, was also responsible for treatment resistance and the expression of genes related to epithelial-mesenchymal plasticity.
Here, benzaldehyde prevented 14-3-3ζ-dependent phosphorylation of the serine28 amino acid of histone H3. Consequently, benzaldehyde treatment reduced the expression of genes responsible for treatment resistance. Treatment of mice with a benzaldehyde derivative inhibited the growth of pancreatic tumors and suppressed the epithelial-to-mesenchymal plasticity, thus preventing the spread of cancer to distant organs like the lungs.
By blocking an interaction key to cancer cell survival, benzaldehyde overcomes therapy resistance and prevents metastasis. Sharing the implications of their findings, Dr. Saya concludes, "The 14-3-3ζ protein has long been considered a target for cancer therapy, but its direct inhibition is not feasible due to its important functions in normal cells. Our results suggest that inhibition of the interaction between 14-3-3ζ and its client proteins by benzaldehyde has the potential to overcome the problem."
The present study shows benzaldehyde is effective against cancer cells that have acquired resistance to radiation and tyrosine kinase inhibitors commonly used in cancer treatment. In the long term, this study suggests its potential as a combinatorial anticancer agent, alongside molecular-targeted therapies.
Dr. Jun Saito is a researcher in the laboratory of Dr. Hideyuki Saya, Oncology Innovation Center, Fujita Health University. She obtained her Ph.D. from the Nihon University Graduate School of Medicine. Continuing the legacy of one of her parents, who pioneered the breakthrough research on the anticancer activity of benzaldehyde in the 1980s, Dr. Saito has uncovered the underlying mechanism of benzaldehyde's anticancer effects. Her expertise includes oncology, pathophysiology, immunology, applied physics, and chemistry.
This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (KAKENHI 19K22568).
