From chemo-prevention to epigenetic regulation: The role of isothiocyanates in skin cancer prevention

Skin cancer incidence is rapidly growing over the last decades and is generally divided into malignant melanoma and non-melanoma (NMSC) with the latter being subdivided into squamous (SCC) and basal cell carcinoma (BCC). Among them, melanoma is the most aggressive type with high mortality rates. On the other hand, aberrant gene expression is a critical step towards malignant transformation. To this end, epigenetic modifications like changes in DNA methylation patterns and miRNA expression profile as well as histone modifications are all capable of inducing an altered gene expression profile involved in various cellular cascades including cell cycle, proliferation and apoptosis. In general, there is an interest about the beneficiary effect of various phytochemicals in the prevention and treatment of skin malignancies. Among them, glucosinolates are an important type of compounds, abundant in cruciferous vegetables, which are hydrolysed by an endogenous enzyme called myrosinase to a range of bioactive compounds including isothiocyanates (ITCs). These are the major biologically active products capable of mediating the anti-cancer effect of cruciferous vegetables. Their chemo-preventive action is mainly attributed to a plurality of anti-cancer properties including regulation of the epigenetic machinery. Current evidence supports the view that ITCs are potent compounds in interacting with the epigenome in order to restore the normal epigenetic landscape in malignant cells. This review article summarizes the current state of knowledge on the epigenetic modifications that lead to malignant transformation and the role of ITCs with respect to their ability to restore the epigenetic landscape that contributes to skin carcinogenesis

Allyl isothiocyanate regulates lysine acetylation and methylation marks in an experimental model of malignant melanoma

Objective(s): Isothiocyanates (ITCs) are biologically active plant secondary metabolites capable of mediating various biological effects including modulation of the epigenome. Our aim was to characterize the effect of allyl isothiocyanate (AITC) on lysine acetylation and methylation marks as a potential epigenetic-induced anti-melanoma strategy. Methods: Our malignant melanoma model consisted of i) human (A375) and murine (B16-F10) malignant melanoma as well as of human ii) brain (VMM1) and lymph node (Hs 294T) metastatic melanoma, iii) non-melanoma epidermoid carcinoma (A431) and iv) immortalized keratinocyte (HaCaT) cells subjected to AITC. Cell viability, histone deacetylases (HDACs) and acetyltransferases (HATs) activities were evaluated by the Alamar blue, Epigenase HDAC Activity/Inhibition and EpiQuik HAT Activity/Inhibition assay kits respectively while their expression levels together with those of lysine acetylation and methylation marks by western immunoblotting. Finally, apoptotic gene expression was assessed by an RT-PCR-based gene expression profiling methodology. Results: AITC reduces cell viability, decreases HDACs and HATs activities and causes changes in protein expression levels of various HDACs, HATs, and histone methyl transferases (HMTs) all of which have a profound effect on specific lysine acetylation and methylation marks. Moreover, AITC causes the induction of apoptotic cell death associated with genes involved in various apoptotic cascades. Conclusions: AITC exerts a potent epigenetic effect suggesting its potential involvement as a promising epigenetic-induced bioactive for the treatment of malignant melanoma

The Role of Isothiocyanates as Cancer Chemo-Preventive, Chemo-Therapeutic and Anti-Melanoma Agents

Many studies have shown evidence in support of the beneficial effects of phytochemicals in preventing chronic diseases, including cancer. Among such phytochemicals, sulphur-containing compounds (e.g., isothiocyanates; ITCs) have raised the scientific interest by exerting unique chemo-preventive properties against cancer pathogenesis. ITCs are the major biologically-active compounds capable of mediating the anticancer effect of cruciferous vegetables. Recently, many studies have shown that higher intake of cruciferous vegetables is associated with reduced risk of developing various forms of cancers primarily due to a plurality of effects including i) metabolic activation and detoxification, ii) inflammation, iii) angiogenesis, iv) metastasis and v) regulation of the epigenetic machinery. In the context of human malignant melanoma, a number of studies suggest that ITCs can cause cell cycle growth arrest and also induce apoptosis in human malignant melanoma cells. On such basis, ITCs could serve as promising chemo-therapeutic agents that could be used in the clinical setting to potentiate the efficacy of existing therapies

Synergistic antitumour potency of a self-assembling peptide hydrogel for the local co-delivery of doxorubicin and curcumin in the treatment of head and neck cancer

Combination therapy has been conferred with manifold assets leveraging the synergy of different agents to achieve sufficient therapeutic outcome with lower administered drug doses and reduced side effects. The therapeutic potency of a self-assembling peptide hydrogel for the co-delivery of doxorubicin (DOX) and curcumin (CUR) combination was evaluated against head and neck cancer cells. The dual loaded peptide hydrogel enabled control over the rate of drug release based on drug's aqueous solubility. A significantly enhanced cell growth inhibitory effect was observed after treatment with the combination drug loaded hydrogel formulations compared to the respective combination drug solution. The synergistic pharmacological effect of selected hydrogel formulations was further confirmed with enhanced apoptotic cell response, interference in cell cycle progression and significantly altered apoptotic/anti-apoptotic gene expression profiles obtained in dose levels well below the half-maximal inhibitory concentrations of both drugs. The in vivo antitumour efficacy of the drug loaded peptide hydrogel formulation was confirmed in HSC-3 cell-xenografted SCID mice and visualized with μCT imaging. Histological and TUNEL assay analyses of major organs were implemented to assess the safety of the topically administered hydrogel formulation. Overall, results demonstrated the therapeutic utility of the dual drug-loaded peptide hydrogel as a promising approach for the local treatment of head and neck cancer.</p