Abstract
Cancer cells undergo uncontrolled proliferation resulting from aberrant activity of various cell-cycle proteins. Therefore, despite recent advances in intensive chemotherapy, it is difficult to cure cancer completely. Recently, cell-cycle regulators became attractive targets in cancer therapy. Zingerone, a phenolic compound isolated from ginger, is a nontoxic and inexpensive compound with varied pharmacological activities. In this study, the therapeutic effect of zingerone as an anti-mitotic agent in human neuroblastoma cells was investigated. Following treatment of BE(2)-M17 cells with zingerone, we performed a 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay and colony-formation assay to evaluate cellular proliferation, in addition to immunofluorescence cytochemistry and flow cytometry to examine the mitotic cells. The association of gene expression with tumor stage and survival was analyzed. Furthermore, to examine the anti-cancer effect of zingerone, we applied a BALB/c mouse-tumor model using a BALB/c-derived adenocarcinoma cell line. In human neuroblastoma cells, zingerone inhibited cellular viability and survival. Moreover, the number of mitotic cells, particularly those in prometaphase, increased in zingerone-treated neuroblastoma cells. Regarding specific molecular mechanisms, zingerone decreased cyclin D1 expression and induced the cleavage of caspase-3 and poly (ADP-ribose) polymerase 1 (PARP-1). The decrease in cyclin D1 and increase in histone H3 phosphorylated (p)-Ser10 were confirmed by immunohistochemistry in tumor tissues administered with zingerone. These results suggest that zingerone induces mitotic arrest followed by inhibition of growth of neuroblastoma cells. Collectively, zingerone may be a potential therapeutic drug for human cancers, including neuroblastoma.
Highlights
Cancer is a major cause of death across the world
Human neuroblastoma cell lines SH-SY5Y, BE(2)C, and BE(2)-M17 were treated with zingerone for 24 or 48 h, and cell viability was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays
D, zingerone strongly increased cleavage of caspase-3 and poly (ADP-ribose) polymerase 1 (PARP-1) in BE(2)-M17 cells. These results demonstrate that zingerone dysregulates cell-cycle progression, and induces apoptosis in neuroblastoma cells
Summary
Cancer is a major cause of death across the world. Cancer cells grow in an uncontrollable way and often invade and spread to other parts of the body. Cancer is characterized by uncontrolled cell proliferation resulting from aberrant cell-cycle activity [1]. The mammalian cell cycle is highly organized and tightly controlled. Proliferation depends on progression through gap 0/1 (G0/G1), synthesis (S), gap 2 (G2), and mitosis (M) phases, regulated by various regulator proteins such as cyclin-dependent kinases (CDKs) [2,3,4]. Because aberrant activation of cell-cycle activators is frequently found in human cancers, cell-cycle regulators are considered attractive targets for cancer treatment [1]
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