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Clioquinol induces cell cycle s-phase arrest through the elevation of calcium level in human neurotypic SH-SY5Y cells


Clioquinol is recently considered to be the most promising drug for anti-tumor and treatment of neurodegenerative diseases. However, its mode of action varies from different disease models.In this study, we found that clioquinol inhibited cell growth in human neurotypic SHSY-5Y cells, which was attributed to both S-phase cell-cycle arrest and autophagic cell death. Clioquinol increased the intracellualr contents of iron and zinc as well as calcium by ICP-AES. Staining of Fluo-3 confirmed an increase in the level of calcium. Analysis of clioquinol and metals-binding ability showed that clioquinol was not a chelating agent of calcium ions and the elevation of intracellular calcium content is not achieved by clioquinol as an ionophore. CaCl2 could simulate or even aggravate the cytotoxicity of clioquinol and increased S-phase cell cycle arrest induced by clioquinol in a concentration dependent manner. Staining of acridine orange demonstrated that autophagy induced by clioquinol was not affected by addition of calcium ions. On the contrary, the intracellular calcium ion chelator BAPTA-am abolished the clioquinol-induced S phase arrest and reduced the cell death caused by clioquinol. The WB assay of cycle-related proteins (CDK2, p21 and p27) further confirmed that S phase arrest is positively correlated with the intracelluar calcium elevation, which was due to the alterations of the mRNA and protein levels of calcium pumps (SERCA and SPCA). Taken together, these data indicate that clioquinol regulates the level of intracellular calcium ion to induce the cell cycle S-phase arrest in human SH-SY5Y cells. Our results demonstrate for the first time that increase of intracellular calcium content is one of the mechanisms of clioquinol in the inhibition of human neurotypic SHSY-5Y cells.

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Publication details

The article was accepted on 31 Oct 2019 and first published on 01 Nov 2019

Article type: Paper
DOI: 10.1039/C9MT00260J
Metallomics, 2019, Accepted Manuscript

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    Clioquinol induces cell cycle s-phase arrest through the elevation of calcium level in human neurotypic SH-SY5Y cells

    P. Shi, J. Sun, X. Lv, Q. Zheng, M. Li, Z. Huang and M. Peng, Metallomics, 2019, Accepted Manuscript , DOI: 10.1039/C9MT00260J

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