Cleavage of PARP, an indicator of caspase 3 mediated apoptosis, was also seen in many of these human cancer sellectchem cell lines upon treatment with FLLL32. Interestingly, loss of mes senger RNA and protein expression of survivin, an inhi bitor of apoptosis, as well as decreased STAT3 DNA binding activity was observed in human rhabdomyosar coma cells treated with FLLL32. The concurrent reduction in STAT3 transcriptional activity of targets such as survivin through decreased DNA binding and loss of STAT3 phosphorylation likely both played a role in the reduced survival of OSA tumor cells observed fol lowing exposure to FLLL32. Recent work has shown that expression of high levels of STAT3 in human OSA tumor samples correlated to poor differentiation, metastasis, and lower rates of over all and relapse free survival.

Overexpression of phosphorylated STAT3 in OSA has also been linked to poor prognosis. STAT3 is known to enhance tumor cell invasion, metastasis, and angiogenesis through enhanced expression of VEGF and MMP2. Human patients with OSA whose tumors had higher VEGF expression as shown by immunohistochemistry had a significantly worse prognosis and had lung metastasis. Previous work revealed Inhibitors,Modulators,Libraries that treatment of OSA cell lines with curcumin inhibited their migration. Mouse xenograft models of pancreatic and colorectal cancer treated with curcumin exhibited Inhibitors,Modulators,Libraries suppression of tumor angiogenesis and tumor growth inhibition. In more recent studies, FLLL32 inhibited vascularity and tumor growth in chicken embryo xenografts and reduced tumor volume in mouse xenografts of breast cancer.

Our data demonstrate that in the OSA cell lines we tested, VEGF mRNA and protein and MMP2 mRNA were expressed and treatment with 10 uM FLLL32 downregulated the expression of these STAT3 transcriptional targets following 24 hours of drug expo sure. Interestingly, VEGF mRNA expression appeared to increase Inhibitors,Modulators,Libraries over baseline in both the OSA8 and SJSA lines after curcumin exposure, although this did not correlate with the findings obtained by Western blotting in which VEGF protein was absent in OSA8 cells and unchanged in SJSA cells. The mechanism for this observed discre pancy is not clear, although there are several possible explanations. Curcumin may somehow interfere with translation of VEGF mRNA, directly enhance degrada tion of VEGF protein, or alternatively, given its diversity of Inhibitors,Modulators,Libraries cellular targets, affect proteins other than STAT3 that in turn alters VEGF expression.

Further investigation of these potential mechanisms is needed. Inhibitors,Modulators,Libraries Given the puta tive role of both Baricitinib molecular weight VEGF and MMP2 in the process of tumor growth and metastasis and recent data demon strating the ability of FLLL32 to abrogate breast cancer xenograft growth in mice, future work assessing the effects of FLLL32 in mouse models of OSA is warranted.