Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 188, Issue 4, Pages 981-994Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2017.12.016
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Funding
- NIH [DK24031, CA183764]
- Mayo Clinic
- Clinical Core and Optical Microscopy Core of the Mayo Clinic Center for Cell Signaling in Gastroenterology [P30DK084567]
- Mayo Translational Polycystic Kidney Disease (PKD) Center - National Institute of Diabetes and Digestive and Kidney Diseases grant [P30DK090728]
- Mayo Translational PKD Center Pilot and Feasibility award
- Eileen Creamer O'Neill award from the PKD Foundation
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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 alpha-tubutin 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.
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