New thymidylate synthase inhibitors induce apoptosis in melanoma cell lines
| Autor: | Giulio Gualdi, A. Coppi, Chiara Bernardi, Alberto Giannetti, Maria Paola Costi, Giorgia Bertazzoni, Luisa Benassi, Stefania Giudice, Alberto Venturelli, Tiziana Rossi, Arianna Gelain, Cristina Magnoni |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Apoptosis
DNA Fragmentation Toxicology Thymidylate synthase Metastasis Amino Acid Chloromethyl Ketones chemistry.chemical_compound In vivo Cell Line Tumor medicine In Situ Nick-End Labeling Humans Enzyme Inhibitors neoplasms Melanoma bcl-2-Associated X Protein Antineoplastic drugs Melanoma cell lines Caspase 8 biology General Medicine Thymidylate Synthase medicine.disease Molecular biology In vitro Caspase 9 Comet assay chemistry Proto-Oncogene Proteins c-bcl-2 Antifolate Cancer research biology.protein Folic Acid Antagonists Poly(ADP-ribose) Polymerases Tumor Suppressor Protein p53 |
| Zdroj: | Toxicology in vitro : an international journal published in association with BIBRA. 21(2) |
| ISSN: | 1879-3177 |
| Popis: | 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 to be tested in vitro and in vivo. We investigated the in vitro action of three new experimental antifolate substances (MR7, MR21 and MR36) with a critical target for thymidylate synthase (TS), an essential enzyme for DNA synthesis. The response of two melanoma cell lines (SK-MEL-2 derived from malignant melanoma metastasis and SK-MEL-28 derived from primary malignant melanoma) was examined after treatment with these substances. The antifolate agents induced apoptosis in SK-MEL-2 and SK-MEL-28 cells as confirmed by the TUNEL technique and Comet Assay. Western-blot analysis showed a down-regulation of Bcl-2 protein level and PARP cleavage, otherwise p53 and Bax expressions were not modulated. Moreover, these antifolate-induced apoptosis was accompanied by both pro-caspase-9 and -8 activations. These results were supported by the use of the pan-caspases inhibitor Z-VAD-FMK that almost completely decreased the amount of apoptosis in both the melanoma cell lines treated with antifolate. In conclusion our results show that TS inhibitors are able to induce apoptosis through a caspase-mediated pathway, but without the involvement of the p53/Bax signalling. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect