Abstract
IntroductionGlucosinolates (GLs) are phytochemicals abundant in cruciferous vegetables, which are hydrolysed, by myrosinase, to a range of isothiocyanates (ITCs). These molecules are biologically active metabolites capable of mediating a plurality of anticancer effects including cell cycle arrest, inhibition of proliferation and apoptotic induction. Their wide range of biological properties may be reflected by their ability to interfere with the epigenetic machinery at both DNA and histone levels. The aim of the current study is to investigate how ITCs interact with the epigenetic pathway(s) response in order to induce apoptosis by modifying the expression of key apoptotic genes in an in vitro model of human malignant melanoma.Material and methodsOur in vitro human malignant melanoma model consists of (i) immortalised normal keratinocyte (HaCaT) cells; (ii) malignant melanoma (A375) cells and epidermoid carcinoma (A431) cells subjected to the following ITCs: R, S-Sulforaphane (SFN), Phenethyl Isothiocyanate (PEITC), Benzyl Isothiocyanate (BITC), Allyl Isothiocyanate (AITC) and Iberin (IBN) over different concentrations and time points of exposure. Apoptotic induction was confirmed by TaqMan qPCR gene expression profiling arrays while involvement of the epigenetic machinery was assessed by western immunoblotting for determining protein expression levels of histone deacetylases (HDACs), histone acetyltransferases (HATs) and various other histone modification tags.Results and discussionsOur results showed that all ITCs were capable of inducing apoptosis as evident by the differential expression of key target genes in a manner where PEITC and IBN were involved primarily in up-regulation compared to SFN and AITC both of which were involved in down-regulation of the majority of these apoptotic genes. Finally, differences in HDAC and HAT protein expression levels, among ITC treatments, were evident in addition to their differential compartmentalization between nucleus and cytosol.ConclusionOverall our results suggest an ITC-dependent cytotoxicity effect which is mediated via apoptotic induction and is underlined, at least partially, by epigenetic pathway(s) response mechanism(s). Our data support the notion that ITCs may be promising candidates in the context of epigenetic therapy for the treatment of human malignant melanoma.
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