Therapeutic effects of 1,4,5-Oxathiazinane-4,4-dioxide on primary & metastatic melanoma cells, fibroblasts and cellular immune responses in vitro

Residual disease in tissue adjacent to melanoma tumours is targeted for removal by wide local excision surgery to reduce recurrence. However, the incidence of melanoma recurrence remains at 20-40% within 5 years. This preclinical investigation evaluated 1,4,5-oxathizinane-4,4-dioxide (OTD), a Taurolidine derivative, and its anti-neoplastic effects on primary and metastatic melanoma cells and impact on immune cell and Human Dermal Fibroblasts (HDF) viability and functionality. The cytotoxic effect of OTD was assessed in primary and metastatic melanoma cells and HDFs using MTT and Annexin V/PI assays. The effect of OTD on wound healing by HDFs was assessed using a migration assay and cytokine production by HDFs was assessed in culture supernatant by electrochemiluminescence. The effect of OTD on cell viability and cytokine production was assessed in cytotoxic lymphocytes (CTLs) by flow cytometry. Although the viability of HDFs was unaffected at all concentrations OTD, wound closure capacity and levels of secreted IL-6 and IL-8 were maintained up to a concentration of 0.75 mM OTD and reduced at higher concentrations of OTD. However, at all concentrations of OTD the production of IFNγ was significantly reduced in CD8⁺ T cells. OTD demonstrated significant ( p < 0.01) cytotoxicity towards two primary melanoma cell lines (A375& WM3248) and two metastatic melanoma cell lines (WM164 & SK-MEL-2) at 1.25 mM OTD. Concentrations of OTD that were cytotoxic to melanoma cells, were not cytotoxic to HDFs and immune cells, however, functionality of HDFs and immune cells were reduced at these concentrations of OTD. Our data suggest the potential for OTD as an adjuvant treatment with surgery for melanoma and support further preclinical investigations.