CCG-222740 is a Rho/MRTF pathway inhibitor. It decreases the activation of stellate cells in vitro and in vivo, by reducing the levels of alpha smooth muscle actin (α-SMA) expression. It also modulates inflammatory components of the pancreas in KC mice (LSL-KrasG12D/+; Pdx-1-Cre) stimulated with caerulein.
In fibroblasts, the Rho/myocardin-related transcription factor (MRTF) pathway has classically been associated with cell contractility, and CAFs (Cancer associated fibroblasts) rely on this pathway to generate tracks for cancer cell migration. This pathway is implicated in the hyper-activation of fibroblasts in fibrotic diseases and the activation of pancreatic stellate cells. CCG-222740, a small molecule, is designed as a Rho/MRTF pathway inhibitor. PSCs (Pancreatic stellate cells), isolated as previously described from the pancreas of wild type C57BL/6 mice, were cultured for 3 days to achive confluence and then treated with CCG-222740 for 6 days. Treatment with 1 μM of CCG-222740 significantly (p < 0.05) reduced the levels of α-SMA (α smooth muscle actin; a marker for stellate cell activation) and collagen 2 A levels in the PSCs. CAFs isolated from a mouse pancreatic tumor induced by a Kras mutation were treated with several concentrations of CCG-222740 for 72 hours. This treatment decreased cell viability of CAFs, with an IC50 of ~10 μM, as measured by the MTT assay. CCG-222740 also had growth inhibitory effects on human and mouse pancreatic cancer cells, inducing growth arrest at similar concentrations as the CAFs. Moreover, CCG-222740 increased the protein levels of p27 and decreased cyclin D1, while the levels of collagens I, 2a and IV, as well as α-SMA in the CAFs were decreased after treatment with CCG-222740 for 72 hours. In vivo, CCG-222740 (100 mg/kg daily) by oral gavage significantly reduced α-SMA levels in the pancreas of caerulein-stimulated KC mice (p < 0.05)[1].
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