TW-37, a nonpeptidic small-molecule inhibitor of Bcl-2, inhibits cell invasion and angiogenesis in pancreatic cancer Free

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Bcl-2 family of proteins plays critical roles in human cancers, including pancreatic cancer, suggesting that the discovery of specific agents targeting Bcl-2 family proteins would be extremely valuable for pancreatic cancer therapy. We have previously reported the synthesis and characterization of TW-37, which seems to be a negative regulator of Bcl-2. In the present investigation, we tested our hypothesis whether TW-37 could be an effective inhibitor of cell growth, invasion and angiogenesis in pancreatic cancer cells. Using multiple cellular and molecular approaches such as MTT assay, apoptosis ELISA assay, flow cytometry, Real-time RT-PCR, Western blotting, EMSA for measuring DNA binding activity of NF-κB, Bcl-2 plasmid transfection, migration, invasion and angiogenesis assays, we found that TW-37 inhibited cell growth in a dose- and time-dependent manner and caused S phase arrest. This was accompanied by increased apoptosis and concomitant attenuation of NF-κB, and down regulation of NF-κB downstream genes such as MMP-9 and VEGF, resulting in the inhibition of pancreatic cancer cell migration, invasion and angiogenesis in vitro and caused anti-tumor activity in vivo. From these results, we conclude that TW-37 is a potent inhibitor of progression of pancreatic cancer cells, which could be due to attenuation of Bcl-2 cellular signaling processes. Our findings provide evidence showing that TW-37 could act as a small-molecule Bcl-2 inhibitor on a well-defined pancreatic cancer cells in culture as well as when grown as tumor in a xenograft model. We also suggest that TW-37 could be further developed as a potential therapeutic agent for the treatment of pancreatic cancer.