Pre-clinical assessment of A-674563 as an anti-melanoma agent
| Autor: | Xuemin Wang, Guo-Biao Fan, Ying Zou |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Ceramide Indazoles Pyridines Biophysics P70-S6 Kinase 1 Antineoplastic Agents Apoptosis Mice SCID Biology Cysteine Proteinase Inhibitors Biochemistry 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Cell Line Tumor medicine Cytotoxic T cell Animals Humans Cytotoxicity Molecular Biology Protein kinase B Melanoma Cell Proliferation Severe combined immunodeficiency Cell Biology Lipid signaling medicine.disease Xenograft Model Antitumor Assays Enzyme Activation 030104 developmental biology chemistry 030220 oncology & carcinogenesis Cancer research Drug Screening Assays Antitumor Proto-Oncogene Proteins c-akt |
| Zdroj: | Biochemical and biophysical research communications. 477(1) |
| ISSN: | 1090-2104 |
| Popis: | The present study aims to investigate the anti-melanoma activity by an Akt1 specific inhibitor A-674563. We showed that A-674563 was anti-proliferative and cytotoxic when added to human melanoma cells (A375, WM-115 and SK-Mel-2 lines). A-674563 induced caspase-dependent apoptotic death of human melanoma cells, and its cytotoxicity was inhibited with pre-treatment of caspase inhibitors. Further, A-674563 treatment blocked Akt and its downstream S6 Kinase 1 (S6K1) activation in A375 melanoma cells. Significantly, restoring Akt-S6K1 activation via introduction of constitutively-active Akt1 (ca-Akt1) only partially attenuated A-674563's cytotoxicity against A375 cells. Further, A-674563 induced pro-apoptotic ceramide production in A375 cells. Significantly, sphingosine-1-phosphate (S1P) inhibited A-674563-induced ceramide production and subsequent A375 cell apoptosis. On the other hand, co-treatment with the glucosylceramide synthase (GCS) inhibitor PDMP or the cell permeable short-chain ceramide (C6) potentiated A-674563's cytotoxicity against A375 cells. In vivo, A-674563 oral gavage inhibited A375 xenograft growth in severe combined immunodeficiency (scid) mice. Akt inactivation, caspase-3 activation and ceramide production were also observed in A-674563-treated A375 xenografts. Together, these results suggest that A-674563 exerts potent anti-melanoma activity, involving Akt-dependent and Akt-independent mechanisms. |
| Databáze: | OpenAIRE |
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