The importance of Cyclophilins and Mps1 in cancer

Sammanfattning: Hepatic fibrosis is a pathological response to chronic liver injuries such as chronic alcohol consumption, non-alcoholic fatty liver disease (NAFLD) or chronic viral infections. No antifibrotic compound has been approved for liver fibrosis and if the cause of the chronic injury is not solved, fibrosis can progress to cirrhosis. Currently the only treatment for liver cirrhosis is liver transplantation. Cirrhosis is associated with increased risk in the development of hepatocellular carcinoma (HCC), the most common primary liver cancer. Cyclophilins are intracellular proteins with the capacity to catalyse the cis/trans isomerization of the peptide bonds at the proline residues facilitating protein folding and conformational changes affecting the function of the targeted proteins. Cyclophilin overexpression is a common event in fibrotic tissues playing a key role in different stages of the fibrotic process, including inflammation, hepatocyte death, and activation of the hepatic stellate cells leading to increased collagen production. We investigated the antifibrotic effect of NV556, a novel potent sanglifehrin-based cyclophilin inhibitor in vitro and in vivo. NV556 decreased liver fibrosis in two animal models of Non-alcoholic steatohepatitis (NASH), STAM and methionine-choline-deficient (MCD) mice. NV556 treatment in an in vitro 3D human liver Extracellular Matrix (ECM) cultured with a TGFβ1-activated human hepatic stellate cell line led to decreased collagen production. HCC is usually diagnosed at a late stage with few accepted treatments and limited efficacy due to side effects and resistance to the treatment. Overexpression of cyclophilins has been observed in HCC increasing proliferation, metastasis and promoting chemoresistance. Treatment with the novel cyclophilin inhibitor NV651, presented a potent antiproliferative effect in HCC cell lines via cell cycle perturbations arresting cells in the mitotic phase. In addition, NV651 decreased tumour growth in xenograft-mouse model. We could also confirm the safety in normal cells and good oral bioavailability. Several pathways involved in cell cycle and DNA repair were affected upon NV651 treatment. The combination of NV651 and cisplatin, a DNA damage reagent, resulted in a synergistic effect in cell viability, and a significant increase on cell death in HCC cell lines. This combination caused a disturbance in the cell cycle and a decrease in the capacity of the cell to repair interstrand crosslinks. Targeting the cell cycle has been proposed as a therapeutic strategy in cancer treatment with special interest in the mitotic phase. The mitotic kinase monopolar spindle 1 (Mps1) is a key regulator of the Spindle assembly checkpoint, which ensures the correct chromosome segregation. We could confirm the increased polyploidy upon Mps1 inhibition in neuroblastoma cell lines and PDX model, leading to mitotic catastrophe activating the caspase-dependent mitochondrial apoptotic pathway. In addition, Mps1 inhibition decreased tumour growth in a xenograft mouse model. In summary, cyclophilin inhibition in liver fibrosis and HCC could be used as a potential therapeutic strategy, individually or in combination. Inhibition of Mps1 led to a potent cytotoxic effect indicating its potential use as a treatment against neuroblastoma.

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