The combination of an HDAC6 inhibitor and a somatostatin receptor agonist synergistically reduces hepato-renal cystogenesis in an animal model of polycystic liver disease

LORENZO PISARELLO, MJ; MASYUK, TATYANA V; GRADILONE,SERGIO; MASYUK, ANATOLIY I; DING, JINGYI (FRANCESS); LEE, PUI-YUEN; LARUSSO, NICHOLAS F

AMERICAN JOURNAL OF PATHOLOGY

AMER SOC INVESTIGATIVE PATHOLOGY, INC

Lugar: Bethesda ; Año: 2018

0002-9440

<!-- /* Font Definitions */@font-face{font-family:Arial;panose-1:2 11 6 4 2 2 2 2 2 4;mso-font-charset:0;mso-generic-font-family:auto;mso-font-pitch:variable;mso-font-signature:-536859905 -1073711037 9 0 511 0;}@font-face{font-family:Times;panose-1:2 0 5 0 0 0 0 0 0 0;mso-font-charset:0;mso-generic-font-family:auto;mso-font-pitch:variable;mso-font-signature:3 0 0 0 1 0;}@font-face{font-family:"ＭＳ 明朝";panose-1:0 0 0 0 0 0 0 0 0 0;mso-font-charset:128;mso-generic-font-family:roman;mso-font-format:other;mso-font-pitch:fixed;mso-font-signature:1 134676480 16 0 131072 0;}@font-face{font-family:"Cambria Math";panose-1:2 4 5 3 5 4 6 3 2 4;mso-font-charset:0;mso-generic-font-family:auto;mso-font-pitch:variable;mso-font-signature:-536870145 1107305727 0 0 415 0;}@font-face{font-family:Cambria;panose-1:2 4 5 3 5 4 6 3 2 4;mso-font-charset:0;mso-generic-font-family:auto;mso-font-pitch:variable;mso-font-signature:-536870145 1073743103 0 0 415 0;} /* Style Definitions */p.MsoNormal, li.MsoNormal, div.MsoNormal{mso-style-unhide:no;mso-style-qformat:yes;mso-style-parent:"";margin:0cm;margin-bottom:.0001pt;mso-pagination:widow-orphan;font-size:12.0pt;font-family:Cambria;mso-ascii-font-family:Cambria;mso-ascii-theme-font:minor-latin;mso-fareast-font-family:"ＭＳ 明朝";mso-fareast-theme-font:minor-fareast;mso-hansi-font-family:Cambria;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;}.MsoChpDefault{mso-style-type:export-only;mso-default-props:yes;font-family:Cambria;mso-ascii-font-family:Cambria;mso-ascii-theme-font:minor-latin;mso-fareast-font-family:"ＭＳ 明朝";mso-fareast-theme-font:minor-fareast;mso-hansi-font-family:Cambria;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;mso-ansi-language:ES-TRAD;}@page WordSection1{size:612.0pt 792.0pt;margin:70.85pt 3.0cm 70.85pt 3.0cm;mso-header-margin:36.0pt;mso-footer-margin:36.0pt;mso-paper-source:0;}div.WordSection1{page:WordSection1;}-->Hepaticcystogenesis in Polycystic Liver Disease (PLD) is associated with abnormalitiesin multiple cellular processes, including elevated cAMP and over-expression ofhistone deacetylase 6 (HDAC6). We previously showed that disease progression inPCK rats (an animal model of PLD) was attenuated by inhibition of either cAMPor HDAC6. Therefore, we hypothesized that concurrent targeting of HDAC6 andcAMP would synergistically reduce cyst growth. Changes in hepato-renalcystogenesis were examined in PCK rats treated with: (i) a pan-HDAC inhibitor,panobinostat; (ii) three specific HDAC6 inhibitors, ACY-1215, ACY-738 andACY-241; and (iii) a combination of ACY-1215 and the somatostatin receptoranalog, pasireotide. We also assessed effects of ACY-1215 and pasireotide aloneand in combination on: (i) cell proliferation, cAMP production and expressionof acetylated a-tubulin invitro in cultured cholangiocytes; and (ii) thelength of primary cilia and the frequency of ciliatedcholangiocytes in vivo in PCK rats. Panobinostat and all threeHDAC6 inhibitors decreased hepato-renal cystogenesis in PCK rats. ACY-1215 was moreeffective than other HDAC inhibitors and was chosen for combinationaltreatment. ACY-1215+pasireotide combination synergistically reduced cyst growthand increased length of primary cilia in PCKrats. In cultured cystic cholangiocytes, ACY-1215+pasireotide combinationconcurrently decreased cell proliferation and inhibited cAMP levels. These datasuggest that the combination of drugs that inhibit HDAC6 and cAMP may be aneffective therapy in PLD.