Research Article: New aspects of antiproliferative activity of 4-hydroxybenzyl isothiocyanate, a natural H2S-donor

Date Published: March 5, 2018

Publisher: Springer Vienna

Author(s): Halina Jurkowska, Maria Wróbel, Dominika Szlęzak, Ewa Jasek-Gajda.


The effect of 4-hydroxybenzyl isothiocyanate (HBITC), a natural H2S-donor from white mustard seeds (Sinapis alba), on the proliferation of human neuroblastoma (SH-SY5Y) and glioblastoma (U87MG) cells was studied and some aspects of the mechanism of its activity were suggested. The inhibition of both SH-SY5Y and U87MG cell proliferation was associated with an increase in the thiosulfate level, the number of cells with the inactive form of Bcl-2 protein, and with a decrease of mitochondrial membrane potential. Interestingly, HBITC results in downregulation of p53 protein and upregulation of p21 protein levels in SH-SY5Y cells. In the presence of elevated levels of H2S and thiosulfate, the sulfhydryl groups of p53 protein as well as Bcl-2 protein could be modified via HBITC-induced S-sulfuration or by oxidative stress. It seems that the induction of p21 protein level is mediated in SH-SY5Y cells by p53-independent mechanisms. In addition, HBITC-treatment caused downregulation of the level of mitochondrial rhodanese and 3-mercaptopyruvate sulfurtransferase, and consequently increased the level of the reactive oxygen species in SH-SY5Y cells.

Partial Text

Hydrogen sulfide (H2S) is endogenously generated in mammalian cells via enzymatic and non-enzymatic pathways. The enzymatic pathways generate H2S from l-cysteine and L-homocysteine using cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CTH), and cysteine aminotransferase with 3-mercaptopyruvate sulfurtransferase (MPST). H2S can be also produced from d-cysteine by MPST with an earlier conversion by D-amino acid oxidase. Non-enzymatic production of H2S can occur through glutathione-dependent conversations (Szabo and Papapetropoulos 2017; Tkacheva et al. 2017; Rose et al. 2017; Yagdi et al. 2016; Zheng et al. 2015; Zhang et al. 2017a). H2S is oxidized by sulfide quinone oxidoreductase (SQR) into a sulfane sulfur atom, which is next transferred to sulfite forming thiosulfate. Sulfane sulfur atoms from thiosulfate can be transferred to reduced glutathione (GSH) by rhodanese (thiosulfate sulfurtransferase, TST) generating glutathione persulfide (GS-SH). Mitochondrial sulfur dioxygenase converts the sulfane sulfur persulfide forming sulfite. Then, sulfite is oxidized to sulfate by sulfite oxidase or is degraded by SQR to produce thiosulfate (Yagdi et al. 2016; Kabil et al. 2014; Jurkowska et al. 2014).

Natural isothiocyanates, such as sulphoraphene, benzyl isothiocyanate (BEITC), phenethyl isothiocyanate (PEITC), and iberin, have anti-cancer properties on prostate (Pawlik et al. 2017), breast (Lin et al. 2017), colon (Lai et al. 2010), glioma (Zhu et al. 2013; Su et al. 2015), neuroblastoma (Jadhav et al. 2007), leukemia and lung (Gupta et al. 2014b) cancer cells.

4-Hydroxybenzyl isothiocyanate, a natural H2S-donor, exerts the antiproliferative effect on SH-SY5Y and U87MG cells. Changes of mitochondrial TST and MPST levels, an increased ROS level, and changes of the level of cell cycle proteins in HBITC-treated SH-SY5Y cells, but not in U87MG cells, are associated with a lower mitochondrial metabolic capacity (Kim et al. 2015) and with a lower level of GSH (Jurkowska et al. 2017) in SH-SY5Y cells. Downregulation of mitochondrial TST and MPST protein levels in the presence of HBITC can result in an increased ROS level in SH-SY5Y cells (Fig. 8). The sulfhydryl groups of p53 protein could be modified via HBITC-induced oxidative stress in SH-SY5Y cells, what can trigger a decrease in p53 protein level. It is possible that inactivation of p53 protein in HBITC-treated SH-SY5Y cells can be also caused by its S-sulfuration in the presence of high levels of H2S and thiosulfate. Interestingly, it seems that the induction of p21 protein level in SH-SY5Y cells is associated with p53-independent mechanisms. In both (SH-SY5Y and U87MG) cancer cells, HBITC affects a decrease in mitochondrial membrane potential and number of cells with activated Bcl-2 protein (inactivation of Bcl-2 protein via HBITC induced S-sulfuration or oxidative stress) (Fig. 8).Fig. 8The antiproliferative activities of 4-hydroxybenzyl isothiocyanate




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