Combination of a Histone Deacetylase 6 Inhibitor and a Somatostatin Receptor Agonist Synergistically Reduces Hepatorenal Cystogenesis in an Animal Model of Polycystic Liver Disease
| Autor: | Anatoliy I. Masyuk, Pui-Yuen Lee, Maria J. Lorenzo Pisarello, Tatyana V. Masyuk, Sergio A. Gradilone, Jingyi Francess Ding, Nicholas F. LaRusso |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male education Pharmacology Histone Deacetylase 6 Hydroxamic Acids Somatostatin Receptor Agonist Article Pathology and Forensic Medicine 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Tubulin Panobinostat medicine Cyclic AMP Animals Cilia Receptors Somatostatin Receptor Cell Proliferation Somatostatin receptor Cell growth Cysts Polycystic liver disease Liver Diseases Acetylation Drug Synergism HDAC6 medicine.disease Pasireotide Rats Histone Deacetylase Inhibitors Disease Models Animal 030104 developmental biology Pyrimidines chemistry 030211 gastroenterology & hepatology Female Bile Ducts Somatostatin |
| Zdroj: | The American journal of pathology. 188(4) |
| ISSN: | 1525-2191 |
| Popis: | Hepatic cystogenesis in polycystic liver disease (PLD) is associated with abnormalities in multiple cellular processes, including elevated cAMP and overexpression of histone deacetylase 6 (HDAC6). Disease progression in polycystic kidney (PCK) rats (an animal model of PLD) is attenuated by inhibition of either cAMP production or HDAC6. Therefore, we hypothesized that concurrent targeting of HDAC6 and cAMP would synergistically reduce cyst growth. Changes in hepatorenal cystogenesis were examined in PCK rats treated with a pan-HDAC inhibitor, panobinostat; three specific HDAC6 inhibitors, ACY-1215, ACY-738, and ACY-241; and a combination of ACY-1215 and the somatostatin receptor analogue, pasireotide. We also assessed effects of ACY-1215 and pasireotide alone and in combination on cell proliferation, cAMP production, and expression of acetylated α-tubulin in vitro in cultured cholangiocytes and the length of primary cilia and the frequency of ciliated cholangiocytes in vivo in PCK rats. Panobinostat and all three HDAC6 inhibitors decreased hepatorenal cystogenesis in PCK rats. ACY-1215 was more effective than other HDAC inhibitors and was chosen for combinational treatment. ACY-1215 + pasireotide combination synergistically reduced cyst growth and increased length of primary cilia in PCK rats. In cultured cystic cholangiocytes, ACY-1215 + pasireotide combination concurrently decreased cell proliferation and inhibited cAMP levels. These data suggest that the combination of drugs that inhibit HDAC6 and cAMP may be an effective therapy for PLD. |
| Databáze: | OpenAIRE |
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