Resveratrol Derivative Exhibits Marked Antiproliferative Actions, Affecting Stemness in Pancreatic Cancer Cells.
Rosalba FlorioBarbara De FilippisSerena VeschiViviana Di GiacomoPaola LanutiGiulia CatittiDavide BroccoAnnalisa di RienzoAmelia CataldiIvana CacciatoreRosa AmorosoAllessandro CamaLaura De LellisPublished in: International journal of molecular sciences (2023)
Pancreatic cancer (PC) is one of the deadliest malignancies, with an increasing incidence and limited response to current therapeutic options. Therefore, more effective and low-toxic agents are needed to improve PC patients' outcomes. Resveratrol (RSV) is a natural polyphenol with multiple biological properties, including anticancer effects. In this study, we explored the antiproliferative activities of newly synthetized RSV analogues in a panel of PC cell lines and evaluated the physicochemical properties of the most active compound. This derivative exhibited marked antiproliferative effects in PC cells through mechanisms involving DNA damage, apoptosis induction, and interference in cell cycle progression, as assessed using flow cytometry and immunoblot analysis of cell cycle proteins, PARP cleavage, and H2AX phosphorylation. Notably, the compound induced a consistent reduction in the PC cell subpopulation with a CD133 + EpCAM + stem-like phenotype, paralleled by dramatic effects on cell clonogenicity. Moreover, the RSV derivative had negligible toxicity against normal HFF-1 cells and, thus, good selectivity index values toward PC cell lines. Remarkably, its higher lipophilicity and stability in human plasma, as compared to RSV, might ensure a better permeation along the gastrointestinal tract. Our results provide insights into the mechanisms of action contributing to the antiproliferative activity of a synthetic RSV analogue, supporting its potential value in the search for effective and safe agents in PC treatment.
Keyphrases
- insulin resistance
- cell cycle
- respiratory syncytial virus
- metabolic syndrome
- dna damage
- cell proliferation
- respiratory tract
- oxidative stress
- type diabetes
- flow cytometry
- single cell
- induced apoptosis
- end stage renal disease
- cell therapy
- newly diagnosed
- endoplasmic reticulum stress
- risk factors
- ejection fraction
- chronic kidney disease
- epithelial mesenchymal transition
- cell death
- diabetic rats
- signaling pathway
- mesenchymal stem cells
- combination therapy
- weight loss
- transcription factor
- replacement therapy
- smoking cessation
- peritoneal dialysis