Pancreatic neoplasia is the fifth most common cancer in the United States with >28,000 newly diagnosed cases per year with an annual mortality rate of greater than 99%. Its etiology is largely unknown and no curative treatment is presently available. In pancreatic cancer, several important survival molecules such as EGFR, NF-kB, COX-2, and Bcl-xL are highly activated. NF-kB regulates many genes involved in tumor progression, survival, angiogenesis and invasion such as Bcl-xL, COX-2, VEGF, MMP-9 and uPAR. High expression of anti-apoptotic Bcl-xL protein promotes cell survival and plays a key role in pancreatic cancer progression leading to drug resistance. Its expression was found in 90% of pancreatic cancer. The overexpression of the cyclooxygenase-2 (COX-2) enzyme in pancreatic cancer has also been shown to contribute to growth, metastasis, and chemoresistance. Therefore, inhibitions of NF-kB, Bcl-2/Bcl-xL, and COX-2 should serve as a novel treatment strategy for pancreatic cancer. Our co-investigator has designed non-peptide, drug-like, cell permeable potent small molecule inhibitors (SMI) that bind to the pocket of Bcl-2 and Bcl-xL and block/disrupt their anti-apoptotic function. These SMI were tested in an in vitro binding assay and found to be potent inhibitor of the binding of Bak BH3 peptide to Bcl-2 and Bcl-xL. We have also shown that genistein inactivates NF-kB and down regulates Bcl-xL, VEGF, MMP-9, and uPAR by transcriptional inactivation. Furthermore, the inhibition of COX-2 activity and Akt/NF-kB by celecoxib could be potentially useful in killing pancreatic cancer cells. We have found that human pancreatic cancer cell lines are notable for high expression of Bcl-XL, NF-kB, and COX-2. Therefore, we hypothesize that targeting the Bcl-2/Bcl-xL survival pathway by SMI and inactivating NF-kB-induced Bcl-2/BcI-xL/COX-2 generation by genistein and celecoxib could be novel therapeutic strategies for the treatment of pancreatic cancer. Of importance to this work is that NF-kB transcriptionally regulates the expression of Bcl-xL, hence inactivation of NF-kB by genistein and treatment with SMI will lead to decreased Bcl-xL. Moreover, the addition of celecoxib may be very useful for inducing pancreatic cancer cell death by inhibiting NF-kB as well as transcription and enzyme activity of COX-2.
Our Specific Aims are: 1) To investigate the molecular mechanisms by which SMI promote apoptosis in human pancreatic cancer cell lines, 2) To determine anti-tumor activity of SMI using human pancreatic cancer xenograft model, 3) To determine whether transcriptional repression of Bcl-xL by genistein will synergize SMI-induced apoptosis in vitro and in vivo, and 4) To determine the effects of inhibition of COX-2 by celecoxib on Akt/NF-kB activation in genistein-treated and SMI-treated pancreatic cancer cells in vitro and in SCID mouse xenograft models. Targeting Bcl-2/Bcl-xL, NF-kB and COX-2 could be novel therapeutic treatment of pancreatic cancer.
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