Given the number of targets affected by curcumin and its poor bioavailabil ity, efforts have been directed kinase inhibitor Erlotinib at improving Inhibitors,Modulators,Libraries its chemical properties by complexing it with lipidsphospholipids and developing more specific derivatives. Interestingly, many of these analogues have demonstrated greater stability and more potent activity against several tumor cell lines, including those derived from breast, prostate, pancreas, and colon cancers when compared to curcumin. Curcumin has been found to be well tolerated in healthy individuals and OSA patients, most recently when given as a solid lipid particle formulation. However, peak plasma levels reached only 22. 43 ngmL, well below concentrations known to have biologic effects against OSA cells in vitro.
During the development of novel curcumin analogs, our collaborators determined that one of these com pounds, FLLL32, was particularly effective at suppres sing the growth of pancreatic and breast cancer cells. To produce FLLL32, the two hydrogen atoms on the central carbon of curcumin were replaced with a spiro cyclohexyl Inhibitors,Modulators,Libraries ring. It was proposed that this altera tion would confer greater stability and specificity for STAT3 than curcumin. Recent work with FLLL32 showed that it induced apoptosis in human melanoma, multiple myeloma, glioblastoma, pancreatic, breast, and colorectal cancer cell lines and inhibited STAT3 phosphorylation and DNA binding. The com pound also exhibited higher potency at inhibiting prolif eration and STAT3 DNA binding activity than curcumin and other JAKSTAT3 inhibitors in human rhabdomyosarcoma cells.
Indeed, FLLL32 has been shown to be more potent than other STAT3 inhibitors in promoting growth inhibition of multiple cancer cell lines, and the drug is improved in its specificity as demonstrated by kinase profile assays that revealed almost Inhibitors,Modulators,Libraries no activity against tyrosine kinases such as Lck, Syk, Lyn, Yes, and Abl 1. Given the superior speci ficity and efficacy of FLLL32 as compared to curcumin in a variety of cancer cell lines, the purpose of this study was to evaluate the biologic activity of this com pound against OSA cell lines. Previous studies have explored the activity of curcu min against OSA both in vitro and in human clinical trials. OSA cell lines experienced cell cycle arrest, reduced proliferation, and underwent apoptosis following treatment with curcumin.
Prior work in our laboratory demonstrated that Inhibitors,Modulators,Libraries STAT3 is constitutively activated in OSA cell lines and that inhibi tion of STAT3 through STAT3 siRNAs or the small Inhibitors,Modulators,Libraries molecule STAT3 inhibitor LLL3 resulted in loss of pro liferation and apoptosis. Data presented in this study showed that FLLL32 inhibited proliferation of OSA cell lines and Dasatinib chemical structure promoted apoptosis via caspase 37 activation at lower concentrations than curcumin.