Pancreatic cancer is one of the most lethal cancers, is characterized by a strong fibro-inflammatory reaction composed mainly of cancer-associated fibroblasts. Pancreatic stellate cells (PSCs) present in the pancreas tumor microenvironment. PSCs can excrete essential amino acids and cytokines to maintain an immunosuppressive environment.
CCG-222740 is a potent and selective Rho/myocardin-related transcription factor (MRTF) pathway inhibitor.
CCG-222740 also is a potent inhibitor of alpha-smooth muscle actin protein expression. It effectively reduces fibrosis in the skin and blocks melanoma metastasis.
In vitro, firstly, in C57BL/6 pancreas mice isolated stellate cells, CCG-222740 reduces the levels of α-SMA and collagen 2 A levels at 1 μM. Fasudil is a nonspecific ROCK inhibitor and also has an inhibitory effect on protein kinases. It can reduce the activation of stellate cells.
Nextly, in CAF cells, CCG-222740 decreases CAF cell viability with an IC50 of 10 μM. And, it has inhibitory effects on human and mouse pancreatic cancer cells. besides, the compound at low concentrations deregulates collagens I, 2a and IV, as well as α-SMA expression in CAF cells. CCG-222740 leads to the exclusion of MRTF from the nucleus, showing a small accumulation of MRTF in the nucleus.
Caerulein can stimulate smooth muscle contraction and is commonly used to induce either acute or chronic pancreatitis. In vivo, in pancreatic cancer mouse models, caerulein promotes disease progression.CCG-222740 (oral gavage; 100 mg/kg; 7 days) prominently reduces α-SMA levels in KC mice(LSL-KrasG12D/+; Pdx-1-Cre). As well as, this down-regulation occurs in the stellate cells surrounding the acinar structures.
CCG-222740 has anti-inflammatory properties. CCG-222740 exhibits a significant up-regulation in the percentage of CD4 T cells (CD45+, CD3+, CD4+) infiltrating into the pancreas. At the same time, it decreases the percentage of macrophages (CD45+, CD11b+, Gr1–) in the pancreas-treated KC mice (12.2%) compared with the control mice (14.4%).
In conclusion, CCG-222740 decreases the activation of stellate cells in vitro and in vivo.
reference:
Leal AS, et al. Sci Rep. 2019 May 8;9(1):7072.