Biological evaluation of MR36, a novel non-polyglutamatable thymidylate synthase inhibitor that blocks cell cycle progression in melanoma cell lines
| Autor: | Maria Paola Costi, Alberto Venturelli, Cristina Magnoni, Paola Azzoni, Daria Morini, Silvia Pirondi, Stefania Seidenari, Stefania Giudice, Eugenia Veratti, Giorgia Bertazzoni, Luisa Benassi |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Cell cycle checkpoint Blotting Western Apoptosis Biology Models Biological Retinoblastoma Protein Thymidylate synthase chemistry.chemical_compound Thymidylate synthase inhibitor Coumarins Cell Line Tumor medicine Humans Cyclin D1 Pharmacology (medical) RNA Messenger Enzyme Inhibitors Phosphorylation Melanoma Pharmacology Caspase 3 Cell Cycle Thymidylate Synthase Cell cycle medicine.disease G1 Phase Cell Cycle Checkpoints Cell biology Gene Expression Regulation Neoplastic Polyglutamic Acid Oncology chemistry Antifolate biology.protein Folic Acid Antagonists Nolatrexed Tumor Suppressor Protein p53 melanoma apoptotic agents anticancer naphtaleins Signal Transduction |
| Popis: | Melanoma is one of the most common cancers, and its incidence has continued to increase over the past few decades. Chemotherapy resistance and related defects in apoptotic signaling are critical for the high mortality of melanoma. Effective drugs are lacking because apoptosis regulation in this tumor type is not well understood. The folate pathway has been considered an interesting target for anticancer therapies, and approaches targeting this pathway have recently been extended to melanoma treatment. In this study, the intracellular apoptosis signaling pathways of two melanoma cells lines (SK-MEL-2 and SK-MEL-28) were investigated after treatment with a new experimental antifolate substance (MR36) that targets thymidylate synthase. In both melanoma cell lines, apoptosis induction was triggered by a p53-independent mechanism. MR36-induced apoptosis was associated with a loss of both mitochondrial membrane potential and caspase-3 activation. Induction of cell cycle arrest by MR36 was associated with changes in the expression of key cell cycle regulators, such as p21 and cyclin D1, and the hypophosphorylation of pRb. In addition, Fas signaling was also analyzed. These findings suggest that, unlike classical antifolates, MR36 exerted an inhibitory effect on both the enzymatic function and expression of thymidylate synthase, thereby inducing apoptosis through the activation of the extrinsic and intrinsic pathways in the melanoma cell lines. MR36 showed a different mechanism of action from the known antifolates (Nolatrexed and Pemetrexed) that resulted in higher anticancer activity. Therefore, MR36 should be included as a potential new therapeutic treatment in melanoma research. |
| Databáze: | OpenAIRE |
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