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

Author(s):

Ana Obradović, Miloš Matić, Branka Ognjanović, Nenad Vuković, Milena Vukić, Predrag Đurđević, Gordana Ušćumlić, Bojan Božić and Biljana B. Nedeljković*   Pages 1491 - 1502 ( 12 )

Abstract:

<P>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. </P><P> Objective: The aim of this study was to evaluate the possible anti-tumor mechanisms of a series of newly synthesized 3-(4-substituted benzyl)-5-isopropyl-5-phenylhydantoin derivatives in different aspects of cell physiology of human colon cancer cell line, HCT-116. </P><P> Methods: The increasing concentrations of derivatives (0.01&#181;M up to 100&#181;M) were applied to cells during 24h, 48h, and 72h after which the evaluation of proliferation, apoptosis, oxidative/anti-oxidative status, nitrite production, and migration/invasion potential of treated cells was performed. </P><P> Results: All tested compounds expressed the dose- and time-dependent anti-proliferative and pro-apoptotic activities against HCT-116 cells. The investigated derivatives induced a decrease in levels of oxidative stress parameters and an increase in levels of nitrite production by treated cells suggesting their significant antioxidative 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. </P><P> Conclusion: The obtained results show the 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.</P>

Keywords:

Hydantoin derivatives, colon cancer cell line, apoptosis, antioxidants, nitric oxide, cell migration.

Affiliation:

Department of Biology and Ecology, Faculty of Science, University of Kragujevac, Kragujevac, Department of Biology and Ecology, Faculty of Science, University of Kragujevac, Kragujevac, Department of Biology and Ecology, Faculty of Science, University of Kragujevac, Kragujevac, Department of Chemistry, Faculty of Science, University of Kragujevac, Kragujevac, Department of Chemistry, Faculty of Science, University of Kragujevac, Kragujevac, Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Department of Organic Chemistry, Faculty of Technology and Metallurgy, University of Belgrade, Belgrade, Institute of Physiology and Biochemistry “Ivan Daja“; Faculty of Biology, University of Belgrade, Belgrade, Institute of Physiology and Biochemistry “Ivan Daja“; Faculty of Biology, University of Belgrade, Belgrade

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