Abstract
Abstract BACKGROUND: Proteasome inhibitors, such as bortezomib and the tetrapeptide ketoepoxide carfilzomib (CFZ), have shown strong antitumor activity in patients with multiple myeloma and non-Hodgkin's lymphoma (NHL). Anti-tumor responses are due to direct tumor cell cytotoxicity but may also involve effects on transcription factors such as signal transducers and activators of transcription (STATs). AIM: To evaluate the effect on STAT phosphorylation in NHL by proteasome inhibitors as a possible mechanism of antitumor activity. METHODS: The human lymphoma cell lines HS-Sultan and Mino were used for this study. In vitro studies involved overnight incubation of cells with DMSO, carfilzomib or ONX 0912 by flow cytometric analysis for STAT3 and STAT5 phosophorylation. In vivo studies, utilized NIH III immunocompromised mice implanted with HS-Sultan cells and single dose administration with carfilzomib or ONX 0912 when tumors reached 200 mm3. Twenty four hours after dosing, tumor cells were isolated by enzymatic digestion and analyzed by flow cytometry. RESULTS: Carfilzomib and ONX 0912 resulted in suppressed STAT3 tyrosine phosphorylation in both cell lines in vitro and in vivo. No effects on the level of STAT5 phosphorylation were detected. CONCLUSION: These findings suggest that carfilzomib and ONX 0912 exert an anti-tumor effect against human B-cell lymphoma in part through alterations in STAT3 phosphorylation levels. This is the first report that proteasome inhibitors can reduce STAT3 activation in human B-cell lymphomas in vivo. These data support the further evaluation of carfilzomib and ONX 0912 as novel therapeutic agents for the treatment of NHL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4796. doi:1538-7445.AM2012-4796
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