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• W2045717811 abstract "Objectives: In pancreatic cancer, several important survival molecules such as EGFR, NF-κB, and Bcl-2 or Bcl-XL are highly activated. Thus, agents that inhibit NF-κB activation, together with agents that directly inhibit Bcl-2 or Bcl-XL protein function, may lead to enhanced cell killing. (−)-Gossypol, a natural polyphenolic compound isolated from cottonseeds, is a dual and potent small-molecule inhibitor of Bcl-2 and Bcl-XL proteins, with a Ki value in the 300-600 nM range for both proteins. Methods: The BxPC-3 human pancreatic cell line was used in this study. (−)-Gossypol was dissolved in DMSO at 20 mmol/L as stock solution, and genistein was dissolved in 0.1 M Na2CO3 to make a 10 mM stock solution. For cell viability, apoptosis, and NF-κB studies, MTT assay, histone/DNA ELISA, and Electrophoretic Mobility Shift Assay (EMSA) were used, respectively. Coimmunoprecipitation experiments were designed to study Bcl-XL/Bim heterodimerization, and Western blots to study cytochrome c release. Results: (−)-Gossypol showed a concentration-dependent growth inhibition effect against BxPC-3 pancreatic cancer cell line and induced apoptosis with no effect on normal peripheral blood lymphocytes. Results from coimmunoprecipitation experiments indicate that the effect of (−)-gossypol is mediated, at least, in part via disrupting the heterodimerization of Bcl-XL with Bim in BxPC-3 pancreatic cancer cells. (−)-Gossypol completely disrupts Bcl-XL/Bim heterodimerization with no change in the total Bcl-XL or Bim protein, indicating that (−)-gossypol treatment does not affect the levels of Bcl-XL and Bim proteins. We have previously shown that genistein, a prominent soy isoflavone, transcriptionally down-regulates Bcl-2, Bcl-XL, VEGF, MMP-9, and uPAR via inhibiting NF-κB activity. In this study, genistein down-regulated NF-κB DNA binding activity and inhibited the growth of BxPC-3 pancreatic cancer cells. In addition, the combination of (−)-gossypol with genistein showed significantly greater growth inhibition compared with either agent alone. Conclusion: From these results, we conclude that inhibition of NF-κB activity and direct inhibition of Bcl-2 or Bcl-XL function should serve as a novel strategy for pancreatic cancer therapy." @default.
• W2045717811 created "2016-06-24" @default.
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• W2045717811 date "2005-11-01" @default.
• W2045717811 modified "2023-09-27" @default.
• W2045717811 title "Nonpeptidic Small-Molecule Inhibitor of Bcl-2 and Bcl-XL, (???)-Gossypol, Enhances Biological Effect of Genistein Against BxPC-3 Human Pancreatic Cancer Cell Line" @default.
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• W2045717811 doi "https://doi.org/10.1097/01.mpa.0000179731.46210.01" @default.
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