New thymidylate synthase inhibitors induce apoptosis in melanoma cell lines

摘要: Malignant melanoma is particularly resistant to conventional chemotherapy and radiotherapy. For this reason in the past years a huge variety of new compounds has been developed with potential chemotherapeutic activity which needs be tested vitro vivo. We investigated action three experimental antifolate substances (MR7, MR21 MR36) critical target for thymidylate synthase (TS), an essential enzyme DNA synthesis. The response two cell lines (SK-MEL-2 derived from malignant metastasis SK-MEL-28 primary melanoma) was examined after treatment these substances. agents induced apoptosis SK-MEL-2 cells as confirmed by TUNEL technique Comet Assay. Western-blot analysis showed down-regulation Bcl-2 protein level PARP cleavage, otherwise p53 Bax expressions were not modulated. Moreover, antifolate-induced accompanied both pro-caspase-9 -8 activations. These results supported use pan-caspases inhibitor Z-VAD-FMK that almost completely decreased amount treated antifolate. In conclusion our show TS inhibitors are able induce through caspase-mediated pathway, but without involvement p53/Bax signalling.