Cell-based high-throughput screen for small molecule inhibitors of Bax translocation
| Autor: | Chesarahmia Dojo Soeandy, Stephano Chang, Jeffrey T. Henderson, Alessandro Datti, Kelvin Hui, Thomas Sun, Frederick S. Vizeacoumar |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Programmed cell death Green Fluorescent Proteins Cell cell-based assay CHO Cells Mitochondrion Small Molecule Libraries 03 medical and health sciences Cricetulus 0302 clinical medicine small molecular inhibitor In vivo bax otorhinolaryngologic diseases medicine Animals Humans high-throughput screen programmed cell death inhibitor cell‐based assay apoptosis in vivo Molecular Medicine Cell Biology Cell Proliferation bcl-2-Associated X Protein high‐throughput screen Chemistry Neurodegeneration Original Articles medicine.disease Molecular medicine In vitro High-Throughput Screening Assays 3. Good health Cell biology Protein Transport 030104 developmental biology medicine.anatomical_structure Apoptosis 030220 oncology & carcinogenesis Original Article |
| Zdroj: | Journal of Cellular and Molecular Medicine |
| Popis: | Aberrant regulation of programmed cell death (PCD) has been tied to an array of human pathologies ranging from cancers to autoimmune disorders to diverse forms of neurodegeneration. Pharmacologic modulation of PCD signalling is therefore of central interest to a number of clinical and biomedical applications. A key component of PCD signalling involves the modulation of pro‐ and anti‐apoptotic Bcl‐2 family members. Among these, Bax translocation represents a critical regulatory phase in PCD. In the present study, we have employed a high‐content high‐throughput screen to identify small molecules which inhibit the cellular process of Bax re‐distribution to the mitochondria following commitment of the cell to die. Screening of 6246 Generally Recognized As Safe compounds from four chemical libraries post‐induction of cisplatin‐mediated PCD resulted in the identification of 18 compounds which significantly reduced levels of Bax translocation. Further examination revealed protective effects via reduction of executioner caspase activity and enhanced mitochondrial function. Consistent with their effects on Bax translocation, these compounds exhibited significant rescue against in vitro and in vivo cisplatin‐induced apoptosis. Altogether, our findings identify a new set of clinically useful small molecules PCD inhibitors and highlight the role which cAMP plays in regulating Bax‐mediated PCD. |
| Databáze: | OpenAIRE |
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