Archives2019Vol. 59, No. 2pp. 214-221

Article

Inhibition of DNA Double Strand Break Repair by Niclosamide in Human Colorectal Cancer Cells

Zhirnik A.S., Semochkina Y.P., Moskaleva E. Yu.

National Research Center “Kurchatov Institute”, Moscow, Russia

Abstract

This study is aimed to investigate the radiosensitizing activity of niclosamide against SW837 human rectal adenocarcinoma and COLO 320 HSR human sigmoid colon carcinoma cells and underlying molecular mechanisms. Cancer cells were exposed to niclosamide, γ-radiation, or combination of both and a cell survival assay was performed. The levels of MDR1, Bcl-2, β-catenin and histone γH2AX, a marker of DNA double strand breaks (DSB), were assessed by flow cytometry after immunocytochemical staining. Combination of niclosamide and γ-irradiation led to a more significant decrease in cancer cell survival compared to niclosamide and γ-irradiation alone. Niclosamide decreased β-catenin levels in COLO 320 HSR cells, and combination of niclosamide and γ-irradiation had more profound effects on β-catenin expression. In contrast, β-catenin levels remained unchanged in SW837 cells exposed to niclosamide, γ-radiation, or their combination. Niclosamide neither induced DNA DSB in non-irradiated cells nor enhanced the DNA damage 1 h after irradiation. However, a combined treatment by niclosamide and γ-irradiation led to an increase in the γH2AX level 24 h after exposure, which remained 1.6-fold higher than in the control and irradiated cells, indicating inhibition of the γ-radiation-induced DNA DSB repair. These results suggest that niclosamide may sensitize human colorectal cancer cells to ionizing radiation by inhibiting DNA DSB repair. Inhibition of Wnt/β-catenin signaling by niclosamide was not observed in all cancer cell types.

Keywords

Niclosamide, DNA double strand breaks, DNA repair, γH2AX, β-catenin, radiosensitizers, ionizing radiation, rectal adenocarcinoma, sigmoid colon carcinoma

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