Combination of a Histone Deacetylase 6 Inhibitor and a Somatostatin Receptor Agonist Synergistically Reduces Hepatorenal Cystogenesis in an Animal Model of Polycystic Liver Disease

Maria Lorenzo Pisarello, Tatyana V. Masyuk, Sergio A. Gradilone, Anatoliy I. Masyuk, Jingyi F. Ding, Pui Yuen Lee, Nicholas F La Russo

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)981-994
Number of pages14
JournalAmerican Journal of Pathology
Volume188
Issue number4
DOIs
StatePublished - Apr 1 2018

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Somatostatin Receptors
Histone Deacetylase Inhibitors
Polycystic Kidney Diseases
Histone Deacetylases
Animal Models
Cilia
Cysts
Cell Proliferation
Multiple Abnormalities
Drug Combinations
Tubulin
Growth
Disease Progression
2-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide
Polycystic liver disease
pasireotide
Liver

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Combination of a Histone Deacetylase 6 Inhibitor and a Somatostatin Receptor Agonist Synergistically Reduces Hepatorenal Cystogenesis in an Animal Model of Polycystic Liver Disease. / Lorenzo Pisarello, Maria; Masyuk, Tatyana V.; Gradilone, Sergio A.; Masyuk, Anatoliy I.; Ding, Jingyi F.; Lee, Pui Yuen; La Russo, Nicholas F.

In: American Journal of Pathology, Vol. 188, No. 4, 01.04.2018, p. 981-994.

Research output: Contribution to journalArticle

Lorenzo Pisarello, Maria ; Masyuk, Tatyana V. ; Gradilone, Sergio A. ; Masyuk, Anatoliy I. ; Ding, Jingyi F. ; Lee, Pui Yuen ; La Russo, Nicholas F. / Combination of a Histone Deacetylase 6 Inhibitor and a Somatostatin Receptor Agonist Synergistically Reduces Hepatorenal Cystogenesis in an Animal Model of Polycystic Liver Disease. In: American Journal of Pathology. 2018 ; Vol. 188, No. 4. pp. 981-994.
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AU - Masyuk, Tatyana V.

AU - Gradilone, Sergio A.

AU - Masyuk, Anatoliy I.

AU - Ding, Jingyi F.

AU - Lee, Pui Yuen

AU - La Russo, Nicholas F

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AB - 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.

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