Pyrazolo-quinolinone suppresses epithelial-mesenchymal transition by targeting the CXCR4/NF-κB axis in human pancreatic cancer cells.

Pancreatic cancer (PC) is the most lethal type of malignancy with a minimal prognosis. It is often diagnosed at advanced disease stages, when existing therapeutics are largely ineffective. Epithelial-mesenchymal transition (EMT) is a biological phenomenon that enables epithelial cancer cells to acquire a mesenchymal phenotype and provides the cancer cells (including PC cells) with metastatic potential. Therefore, the discovery of small molecules with anti-EMT potential is important for conventional cytotoxic agents, as it may enable the inhibition of tumor progression and metastasis, alongside cytotoxicity. Herein, we investigated the anti-EMT potential of a synthetic pyrazolo-quinolinone derivative (designated RD-20) in PC cells. Biological activity was assessed through cell viability assays, migration/invasion assays, Western blotting, immunocytochemistry for EMT markers, and gelatin zymography. RD-20 exhibited marginal cytotoxicity in PC cells but significantly reduced mRNA and protein expression of chemokine receptors (CXCR4 and CXCR7) and protein levels of MMPs (MMP-2 and MMP-9), correlating with reduced invasive capacity. The expression of mesenchymal markers (Vimentin, Twist, and Snail) was reduced, while expression of epithelial markers (Occludin and E-cadherin) was increased upon RD-20 exposure, which was complemented by the results of immunocytochemistry. Functionally, RD-20 inhibited the invasion and migration of CXCL12-induced PC cells. A mechanistic approach revealed that RD-20 suppresses NF-κB activation, thereby blocking the expression of CXCR4, MMP-2, and MMP-9. Collectively, these findings indicate that RD-20 abrogates the NF-κB activation to induce anti-EMT effects in PC cells.