Pancreatic cancer is extremely deadly due to its rapid resistance to treatments. Overcoming this resistance is crucial for better patient outcomes. Researchers in Japan discovered that aromatic benzaldehyde, a compound with an almond-like scent, can effectively inhibit therapy-resistant pancreatic cancer. Published in the British Journal of Cancer, their study shows that benzaldehyde disrupts vital protein interactions linked to treatment resistance and cancer cell adaptability. Preclinical studies indicate that it can make resistant cells more responsive to radiation and targeted therapies. Additionally, it prevents the epithelial-to-mesenchymal transition, a process that promotes cancer spread.
Pancreatic ductal adenocarcinoma (PDAC) is extremely aggressive, with less than 10% surviving five years. Its poor prognosis is largely due to its ability to resist treatment. Standard treatments—surgery, chemotherapy, radiation, or targeted drugs like tyrosine kinase inhibitors—initially reduce tumors, but remaining cells often return stronger.
Epithelial-to-mesenchymal plasticity (EMP) is crucial for cancer spread and treatment resistance. Under treatment stress, epithelial cancer cells, usually tightly connected, shift to a mesenchymal state. This change boosts their movement, invasiveness, and survival against cell death. EMP aids in spreading to distant organs and helps cancer cells dodge therapeutic attacks.
Finding new agents is crucial to overcoming treatment resistance. In the 1980s, benzaldehyde showed promise as an anticancer agent, but its workings were unclear. Dr. Hideyuki Saya’s team at Fujita Health University’s Oncology Innovation Center aimed to uncover how benzaldehyde kills cancer cells, focusing on tough pancreatic cancer cases.
Benzaldehyde: A Fragrant Compound with Anticancer Activity
Benzaldehyde, found in almonds, apricots, figs, and some flowers, emits a sweet, almond-like scent. It’s used in flavorings and perfumes. Oncologists became interested when studies showed it could stop mouse embryonic cells from multiplying.
Intergenerational Motivation
Dr. Jun Saito, the lead author of the study, is the daughter of a 1980s researcher who discovered benzaldehyde’s anticancer properties. Inspired by her father’s groundbreaking research, Saito aimed to explore the molecular mechanisms of benzaldehyde and evaluate its effectiveness against current therapy-resistant pancreatic tumors.
Mechanism of Action: Disrupting 14-3-3ζ–H3S28ph Interactions
14-3-3ζ is a key protein that connects with many other proteins, controlling cell growth, death, and stress reactions. In many cancers, high levels of 14-3-3ζ are linked to worse outcomes and resistance to treatment.
Histone H3 phosphorylation at serine 28 (H3S28ph) is crucial for quickly activating immediate-early genes, which are vital for processes like epithelial-mesenchymal transition (EMP) and stress responses. In cells resistant to therapy, H3S28ph enhances the transcription of genes that support survival, increase invasiveness, and aid in drug resistance.
Blocking the Critical Interaction
Dr. Saya’s team found that in pancreatic cancer cells resistant to therapy, 14-3-3ζ binds to H3S28ph, anchoring complexes that activate genes linked to resistance. They showed through assays that benzaldehyde treatment stops 14-3-3ζ from binding to H3S28ph. Molecular docking studies indicated that benzaldehyde fits into a crucial pocket on 14-3-3ζ, reducing its affinity for phosphorylated histone tails.
Breaking the 14-3-3ζ–H3S28ph interaction stopped resistant cells from boosting genes for DNA repair, anti-apoptosis, and mesenchymal markers like N-cadherin and vimentin. Tests like quantitative PCR and RNA-Seq showed a major drop in genes for epithelial-to-mesenchymal plasticity and resistance factors such as ABC transporters.
Researchers developed radiation-resistant PDAC cell lines by subjecting parental cells to fractionated ionizing radiation doses. These cells showed strong survival and clonogenicity after irradiation. However, when treated with benzaldehyde at just 50 µM, their radiosensitivity was restored, decreasing survival by over 70% compared to radiation alone.
Benzaldehyde effectively targets PDAC cells resistant to osimertinib, an EGFR inhibitor used in pancreatic cancer trials. Combining these treatments enhances cell-killing effects, with a combination index under 0.5, showing strong synergy. Benzaldehyde blocks resistance gene expression, stopping alternative signaling pathways.
Benzaldehyde treatment halts cells in the G2/M phase and boosts apoptosis. Flow cytometry shows more apoptotic cells through annexin V staining and caspase-3 activation. Western blots reveal increased proapoptotic proteins Bax and cleaved PARP, while antiapoptotic Bcl-2 decreases.
In Vivo Studies: Mouse Xenograft Models
To confirm lab results, researchers implanted radiation and osimertinib-resistant pancreatic cancer cells into mice with weakened immune systems. When tumors grew to 100 mm³, mice were randomly assigned to receive either a placebo, a benzaldehyde derivative injected daily at 20 mg/kg, standard therapy alone, or a combination of treatments.
Tumor Growth Inhibition and Survival Benefits
The benzaldehyde derivative alone reduced tumor growth by about 50%. When combined with radiation or osimertinib, tumor size decreased by over 80% in three weeks. Survival rates improved, with median survival increasing from 28 days in vehicle-treated mice to 60 days in those receiving combination therapy. At the study’s conclusion, 40% of mice were tumor-free.
Autopsies showed widespread lung metastases in control and monotherapy groups. In contrast, mice treated with benzaldehyde, especially those on combination therapy, had few or no metastatic lesions. Immunohistochemistry confirmed lower expression of mesenchymal markers and a reduced proliferative index (Ki-67), supporting the compound’s ability to inhibit EMP in vivo.
Enhancing Radiotherapy and Targeted Agents
Benzaldehyde, when combined with radiation and osimertinib, shows promise as a powerful agent. It targets resistance mechanisms different from DNA damage or kinase inhibition, enhancing current treatments without adding extra toxicity.
Treated mice kept a steady body weight with no major changes in blood or biochemical tests. Examination of key organs—liver, kidney, heart, and spleen—revealed no clear signs of toxicity, indicating a good safety margin at effective doses.
In the 1980s, benzaldehyde was known for its anticancer properties, but its exact targets were unknown. Dr. Saya emphasized this, and Dr. Jun Saito’s connection to the initial research motivated their team to explore benzaldehyde’s mechanisms. Their research reveals that benzaldehyde is more than just a toxic aroma; it disrupts cancer’s ability to adapt.
Implications for Targeting 14-3-3ζ
14-3-3ζ is a known cancer therapy target, but direct inhibitors may harm normal cells where it plays vital roles. Benzaldehyde provides a precise approach by selectively blocking harmful interactions without disrupting essential functions, targeting cancer-specific survival pathways.
Challenges and Next Steps
To transition benzaldehyde derivatives from preclinical success to clinical use, we must refine their effectiveness, absorption, and safety in humans. Medicinal chemistry is focused on improving stability and target interaction. Pharmacokinetic research will establish appropriate dosing schedules.
Biomarker Identification
Pinpointing patient groups that will benefit most is vital. Biomarkers like high 14-3-3ζ expression, H3S28ph levels, or EMP gene signatures can forecast response to benzaldehyde-based treatment. Upcoming clinical trials will include related studies to enhance patient selection.
Early-phase clinical trials will boldly evaluate the safety and initial efficacy of benzaldehyde derivatives as standalone treatments for resistant PDAC and in combination with radiation or targeted therapies. Adaptive trial designs and biomarker-driven cohorts will accelerate assessment and minimize potential risks effectively.
Conclusion
Fujita Health University found that aromatic benzaldehyde can fight therapy-resistant pancreatic cancer. It blocks the 14-3-3ζ–H3S28ph interaction, which causes treatment resistance and cancer cell adaptability. Benzaldehyde restores sensitivity to radiation and kinase inhibitors and stops cancer from spreading. This makes it a promising new anticancer therapy. As it moves toward clinical trials, this fragrant compound could soon provide hope to patients battling one of the toughest cancers to treat.
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