A Combination of Vitamins K3 and C Attenuates Hepatic Cystogenesis in Rodent Models of Polycystic Liver Disease

MARIA LORENZO PISARELLO; TATYANA V. MASYUK; ANATOLIY I. MASYUK; BRYNN N. HOWARD; TOM MILLER; NICHOLAS F. LARUSSO

Congreso; Liver meeting - American Association for the study of liver diseases; 2016

The Polycystic Liver Diseases (PLD) are genetic disorders characterized by fluid-filled hepatic cysts arising from cholangiocytes. Previously, we found that cyst expansion is linked to cell-cycle dysregulation due to overexpression of cell division cycle 25 (Cdc25)A phosphatase. We also reported that a Cdc25A inhibitor, Vitamin K3 (VK3), decreases hepatic cystogenesis in animal models of PLD. Since recent data suggest that VK3 inhibits growth of cancer cells to a greater degree when combined with Vitamin C (VC), our AIM here was to investigate the therapeutic value of a combination of VK3 and VC (VK3:VC) in PLD. METHODS: We assessed cell proliferation and cell cycle distribution in cultured cholangio- cytes and hepatic cystogenesis in vivo in animal models of PLD (PCK rats and Pkd2WS25/- mice) in response to VK3:VC, and VK3 and VC alone. We also examined the effects of VK3:VC on selected biological processes in rat cystic cholangiocytes by gene expression profiling (GEP). RESULTS: VC alone had no effect on cell proliferation or cell cycle distribution in cultured cholangiocytes, or on hepato-renal cystogenesis in vivo. How- ever, VK3:VC decreased proliferation of cystic cholangiocytes by 56% and reduced the number of cells in the S phase of the cell cycle by 35%; these effects were greater (p