Anti-Tumor Mechanisms of Novel 3-(4-Substituted Benzyl)-5-Isopropil-5- Phenylhydantoin Derivatives in Human Colon Cancer Cell Line

Abstract

Background: Hydantoin and its newly synthesized derivatives have recently become a focus of interest due to their numerous biological activities and newly emerging beneficial effects in different pathological conditions, including cancer. Objective: The aim of this study was to evaluate the possible anti-tumor mechanisms of series of newly synthesized 3-(4-substituted benzyl)-5-isopropyl-5-phenylhydantoin derivatives on different aspects of cell physiology of human colon cancer cell line, HCT-116. Method: The increasing concentrations of derivatives (0.01 µM up to 100 µM) were applied to cells during 24 h, 48 h, and 72 h after which the evaluation of proliferation, apoptosis, oxidative/anti-oxidative status, nitrite production, and migration/invasion potential of treated cells were performed. Results: All tested compounds expressed the dose- and time-dependent anti-proliferative and pro-apoptotic activities against HCT-116 cells. The investigated derivatives induced decrease in levels of oxidative stress parameters and increase in levels of nitrite production by treated cells suggesting their significant anti-oxidative effects. The cell migration index and expression level of tumor invasion-promoting metalloproteinase-9 (MMP-9) gene were significantly decreased after treatment with the tested hydantoin derivatives implicating their inhibitory role in colon cancer cell motility and invasion processes. The mRNA level of cyclooxygenase-2 (COX-2) gene as a pro-inflammatory gene related to colorectal carcinogenesis was reduced compared to values in the non-treated control cells indicating the significant anti-inflammatory/anti-tumor effects of these compounds. Conclusion: The obtained results show significant anti-tumor potential of tested derivatives, especially 3-benzyl-5-isopropyl-5-phenylhydantoin and 3-(4-chlorobenzyl)-5-isopropyl-5-phenylhydantoin, suggesting their potential usage in the development of more effective chemotherapies.