nsc-74859 and stattic

Angiotensin II (Ang II) is known to promote vascular disease and hypertension in part by formation of cytokines, such as interleukin-6. However, the role of signal transducer and activator of transcription 3 (STAT3) in these processes and Ang II/interleukin-6 signaling is unclear. Using 2 models, we tested the hypothesis that STAT3 is essential for Ang II-induced vascular dysfunction and hypertension. Incubation of isolated carotid arteries from C57BL/6J mice with Ang II overnight increased superoxide ≈2-fold and reduced vasodilator responses to the endothelium-dependent agonist acetylcholine by ≈50% versus controls (P<0.05). These effects were prevented by the addition of small-molecular inhibitors of STAT3 activation (S3I-201 or STATTIC). In vivo, administration of Ang II (1.4 mg kg(-1) day(-1)) using osmotic minipumps increased arterial pressure by ≈40 mm Hg at day 14 compared with vehicle-treated mice, and this effect was prevented by S3I-201 treatment (5 mg/kg IP, QOD). After systemic treatment with Ang II, dilator responses to acetylcholine were reduced by ≈30% to 50% in carotid artery and basilar arteries, whereas S3I-201 treatment prevented most of this impairment (P<0.05). In contrast to effects on vascular function and blood pressure, S31-201 did not prevent Ang II-induced hypertrophy in the carotid artery. These findings provide the first evidence that inhibitors of STAT3 activation protect against Ang II-induced oxidative stress, endothelial dysfunction, and hypertension. Because Ang II promotes vascular disease in the presence of multiple cardiovascular risk factors, these results suggest that selective targeting of STAT3 may have substantial therapeutic potential.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Aminosalicylic Acids; Angiotensin II; Animals; Antihypertensive Agents; Aorta; Benzenesulfonates; Carotid Arteries; Cyclic S-Oxides; Endothelium, Vascular; Hypertension; Male; Mice; Nitroprusside; Oxidative Stress; Phosphorylation; STAT3 Transcription Factor; Superoxides; Vasoconstrictor Agents; Vasodilator Agents

Pancreatic cancer is a largely incurable disease, and increasing evidence supports strategies targeting multiple molecular mediators of critical functions of pancreatic ductal adenocarcinoma cells. Intracellular redox state modulates the activity of various signal transduction pathways and biological processes, including cell survival, drug resistance and responsiveness to microenvironmental factors. Recently, it has been shown that the transcription factor STAT3 is under redox control, but the mechanisms involved in its regulation are unknown. Here, we demonstrate for the first time that STAT3 DNA binding and transcriptional activity is directly regulated by the redox function of the APE1/Ref-1 endonuclease, using overexpression and redox-specific mutational strategies, and gene knockdown. Also, pharmacological blockade of APE1/Ref-1 by the redox-selective inhibitor E3330 abrogates STAT3 DNA binding. Since APE1/Ref-1 also exerts redox control on other cancer-associated transcription factors, we assessed the impact of dual-targeting of STAT3 signaling and APE1/Ref-1 redox on pancreatic cancer cell functions. We observed that disruption of APE1/Ref-1 redox activity synergizes with STAT3 blockade to potently inhibit the proliferation and viability of human PDAC cells. Mechanistically, we show that STAT3-APE1/Ref-1 dual targeting promotes marked tumor cell apoptosis, with engagement of caspase-3 signaling, which are significantly increased in comparison to the effects triggered by single target blockade. Also, we show that STAT3-APE1/Ref-1 dual blockade results in significant inhibition of tumor cell migration. Overall, this work demonstrates that the transcriptional activity of STAT3 is directly regulated by the redox function of APE1/Ref-1, and that concurrent blockade of STAT3 and APE1/Ref-1 redox synergize effectively inhibit critical PDAC cell functions.

Topics: Adenocarcinoma; Aminosalicylic Acids; Apoptosis; Benzenesulfonates; Benzoquinones; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cyclic S-Oxides; DNA-(Apurinic or Apyrimidinic Site) Lyase; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Molecular Targeted Therapy; Oxidation-Reduction; Pancreatic Neoplasms; Propionates; RNA, Small Interfering; Signal Transduction; STAT3 Transcription Factor; Transcription, Genetic