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Synthetic Conjugates of Ursodeoxycholic Acid Inhibit Cystogenesis in Experimental Models of Polycystic Liver Disease.
Caballero-Camino, Francisco J; Rivilla, Ivan; Herraez, Elisa; Briz, Oscar; Santos-Laso, Alvaro; Izquierdo-Sanchez, Laura; Lee-Law, Pui Y; Rodrigues, Pedro M; Munoz-Garrido, Patricia; Jin, Sujeong; Peixoto, Estanislao; Richard, Seth; Gradilone, Sergio A; Perugorria, Maria J; Esteller, Manel; Bujanda, Luis; Marin, Jose J G; Banales, Jesus M; Cossío, Fernando P.
Affiliation
  • Caballero-Camino FJ; Department of Organic Chemistry I, Center of Innovation in Advanced Chemistry (ORFEO-CINQA), University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU), Donostia International Physics Center (DIPC), Donostia-San Sebastian, Spain.
  • Rivilla I; Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, UPV/EHU, Donostia-San Sebastian, Spain.
  • Herraez E; Department of Organic Chemistry I, Center of Innovation in Advanced Chemistry (ORFEO-CINQA), University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU), Donostia International Physics Center (DIPC), Donostia-San Sebastian, Spain.
  • Briz O; Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain.
  • Santos-Laso A; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain.
  • Izquierdo-Sanchez L; Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain.
  • Lee-Law PY; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain.
  • Rodrigues PM; Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, UPV/EHU, Donostia-San Sebastian, Spain.
  • Munoz-Garrido P; Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, UPV/EHU, Donostia-San Sebastian, Spain.
  • Jin S; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain.
  • Peixoto E; Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, UPV/EHU, Donostia-San Sebastian, Spain.
  • Richard S; Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, UPV/EHU, Donostia-San Sebastian, Spain.
  • Gradilone SA; Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, UPV/EHU, Donostia-San Sebastian, Spain.
  • Perugorria MJ; The Hormel Institute, University of Minnesota, Austin, MN.
  • Esteller M; Masonic Cancer Center, University of Minnesota, Minneapolis, MN.
  • Bujanda L; The Hormel Institute, University of Minnesota, Austin, MN.
  • Marin JJG; Masonic Cancer Center, University of Minnesota, Minneapolis, MN.
  • Banales JM; The Hormel Institute, University of Minnesota, Austin, MN.
  • Cossío FP; Masonic Cancer Center, University of Minnesota, Minneapolis, MN.
Hepatology ; 73(1): 186-203, 2021 01.
Article in En | MEDLINE | ID: mdl-32145077
ABSTRACT
BACKGROUND AND

AIMS:

Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of symptomatic biliary cysts. Current surgical and pharmacological approaches are ineffective, and liver transplantation represents the only curative option. Ursodeoxycholic acid (UDCA) and histone deacetylase 6 inhibitors (HDAC6is) have arisen as promising therapeutic strategies, but with partial benefits. APPROACH AND

RESULTS:

Here, we tested an approach based on the design, synthesis, and validation of a family of UDCA synthetic conjugates with selective HDAC6i capacity (UDCA-HDAC6i). Four UDCA-HDAC6i conjugates presented selective HDAC6i activity, UDCA-HDAC6i #1 being the most promising candidate. UDCA orientation within the UDCA-HDAC6i structure was determinant for HDAC6i activity and selectivity. Treatment of polycystic rats with UDCA-HDAC6i #1 reduced their hepatomegaly and cystogenesis, increased UDCA concentration, and inhibited HDAC6 activity in liver. In cystic cholangiocytes UDCA-HDAC6i #1 restored primary cilium length and exhibited potent antiproliferative activity. UDCA-HDAC6i #1 was actively transported into cells through BA and organic cation transporters.

CONCLUSIONS:

These UDCA-HDAC6i conjugates open a therapeutic avenue for PLDs.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Ursodeoxycholic Acid / Apoptosis / Cysts / Synthetic Drugs / Liver / Liver Diseases Limits: Animals Language: En Journal: Hepatology Year: 2021 Type: Article Affiliation country: Spain
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Ursodeoxycholic Acid / Apoptosis / Cysts / Synthetic Drugs / Liver / Liver Diseases Limits: Animals Language: En Journal: Hepatology Year: 2021 Type: Article Affiliation country: Spain