TW-37, a small-molecule inhibitor of Bcl-2, inhibits cell growth and invasion in pancreatic cancer.
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 this 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 enzyme-linked immunosorbent assay, real-time reverse transcription-polymerase chain reaction, Western blotting, electrophoretic mobility shift assay for measuring DNA binding activity of NF-kappaB, migration, invasion and angiogenesis assays, we found that TW-37, in nanomolar concentrations, inhibited cell growth in a dose- and time-dependent manner. This was accompanied by increased apoptosis and concomitant attenuation of NF-kappaB, and downregulation of NF-kappaB downstream genes such as MMP-9 and VEGF, resulting in the inhibition of pancreatic cancer cell migration, invasion and angiogenesis in vitro and caused antitumor 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 well-characterized 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.
Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA.
Zhiwei
Z
Wang
Wen
W
Song
Amro
A
Aboukameel
Mussop
M
Mohammad
Guoping
G
Wang
Sanjeev
S
Banerjee
Dejuan
D
Kong
Shaomeng
S
Wang
Fazlul H
FH
Sarkar
Ramzi M
RM
Mohammad
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000096:biosynthesis / Q000235:genetics; D020672:I-kappa B Proteins / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000494:pharmacology*; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D001549:Benzamides; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D013450:Sulfones; C515128:TW-37 compound; D042461:Vascular Endothelial Growth Factor A; D051550:I-kappa B Kinase; D020780:Matrix Metalloproteinase 9