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Do iron chelators increase the antiproliferative effect of trichostatin A through a glucose-regulated protein 78 mediated mechanism?

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Tumor Biology

Abstract

Histone deacetylase (HDAC) inhibitors, such as trichostatin A (TSA), and iron chelators, including deferoxamine (DFO) and phenanthroline (PHEN), appear to have anticancer effects. We hypothesized that the HDAC inhibitors and iron chelators would be synergistic with their effect on breast cancer cell line MCF7, because the HDAC inhibitors increase glucose-regulated protein 78 (Grp78) and the iron chelators reduce its expression. Although the administration of TSA alone resulted in a dose-related decrease in the cell index, it did not have an antiproliferative effect except the 62.5 and 500 nM of TSA. However, all doses of TSA produced a cytotoxic effect from the initial hours when combined with 150 μM of DFO and 25 μM of PHEN. DFO and PHEN downregulated Grp78, Grp94, and MRP1 expressions and upregulated CHOP and HO-1 expressions. TSA upregulated all the genes in various rates when used alone but resulted in decreased expression levels when combined with DFO and PHEN. Increased HDAC-1 levels in the Grp78 promoter region indicated that DFO and PHEN either promoted binding of HDAC-1 to this region or inhibited its detachment. We determined that the reduction of increased Grp78, Grp94, HO-1, and MRP1 expressions, which appears to inhibit the chemotherapeutic effect of TSA, through the combination with DFO or PHEN will contribute to the anticancer effect.

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Acknowledgment

This study was supported by the Ondokuz Mayis University. The project number was PYO.TIP. 1901 09 001.

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Authors and Affiliations

  1. Public Health Laboratory, 55139, Kurupelit, Trabzon, Turkey

    Veli Kilinc

  2. Faculty of Medicine, Department of Medical Biochemistry, Ondokuz Mayis University, Samsun, Turkey

    Abdulkerim Bedir, Ali Okuyucu, Osman Salis, Hasan Alacam & Sedat Gulten

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  1. Veli Kilinc
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  2. Abdulkerim Bedir
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  3. Ali Okuyucu
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Correspondence to Ali Okuyucu.

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Kilinc, V., Bedir, A., Okuyucu, A. et al. Do iron chelators increase the antiproliferative effect of trichostatin A through a glucose-regulated protein 78 mediated mechanism?. Tumor Biol. 35, 5945–5951 (2014). https://doi.org/10.1007/s13277-014-1788-1

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  • DOI: https://doi.org/10.1007/s13277-014-1788-1

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