Novel cyclic C5-curcuminoids possess anticancer activities against HeLa cervix carcinoma, HEC-1A adenocarcinoma, and T24 bladder carcinoma cells

Umin was discovered in Curcuma longa L. and/or Curcuma domestica L. C5-curcumin and its derivatives, like synthetic cyclic C5-curcuminoids, are promising anticancer compounds with exceptional pharmacokinetic profiles compared to curcumin. To demonstrate their anticancer activities, we tested six novel synthetic cyclic C5-curcuminoids on HeLa, HEC-1A, and T24 tumor cell lines. This investigation focused on ferroptosis and apoptosis, two types of programmed cell death. Ferroptosis-related genes were investigated using real-time polymerase chain reaction (PCR) and Western blotting. The total iron content, reactive oxygen species (ROS) levels, glutathione peroxidase activity, and thiol concentrations were measured to determine ferroptosis. Cytochrome c levels and caspase-3 activity were measured to monitor the apoptosis. The study of six synthetic cyclic C5-curcuminoids revealed that their effects on HeLa cells differed from those on HEC-1A and T24 cells, indicating distinct mechanisms of action. Compound 4 notably increased iron accumulation and reactive oxygen species (ROS) production, while decreasing antioxidant defenses in all three carcinoma cell lines, suggesting a ferroptotic response. In contrast, compound 9 was successful in activating caspase-3 in carcinoma cells and inducing apoptosis in the COS-1 control cell line. Notably, compound 4 did not enhance caspase-3 activity in the control cell line. These results highlight compound 4 as a possible synthetic cyclic C5-curcuminoid for the three cancerous cell lines tested. Regarding the distinct effects of the examined synthetic cyclic C5-curcuminoids on the three cancer cell types, we hypothesize that their mechanisms of action are different and that divergent target molecules and/or signaling pathways may be involved. However, compounds 4 and 9 were efficient against the three carcinoma cell lines. Further examination of the possible targets could help elucidate which compounds are more suitable for consideration as potential antitumor drug candidates.