nsc-74859 and Esophageal-Neoplasms

c-Hepatocyte growth factor receptor (Met) inhibitors have demonstrated clinical benefits in some types of solid tumors. However, the efficacy of c-Met inhibitors in esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, we discovered that c-Met inhibitors induced "Signal Transducer and Activator of Transcription (STAT3)-addiction" in ESCC cells, and the feedback activation of STAT3 in ESCC cells limits the tumor response to c-Met inhibition. Mechanistically, c-Met inhibition increased the autocrine of several cytokines, including CCL2, interleukin 8, or leukemia inhibitory factor, and facilitated the interactions between the receptors of these cytokines and Janus Kinase1/2 (JAK1/2) to resultantly activate JAKs/STAT3 signaling. Pharmacological inhibition of c-Met together with cytokines/JAKs/STAT3 axis enhanced cancer cells regression in vitro. Importantly, combined c-Met and STAT3 inhibitors synergistically suppressed tumor growth and promoted the apoptosis of tumor cells without producing systematic toxicity. These findings suggest that inhibition of the STAT3 feedback loop may augment the response to c-Met inhibitors via the STAT3-mediated oncogene addiction in ESCC cells.

Topics: Aminosalicylic Acids; Animals; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Drug Resistance, Neoplasm; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Feedback, Physiological; Female; Humans; Male; Mice, Inbred BALB C; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Signal Transduction; STAT3 Transcription Factor; Tyrosine; Xenograft Model Antitumor Assays

Radiotherapy is the main therapy for inoperable and locally advanced esophageal squamous cell carcinoma (ESCC). However, radioresistance in ESCC remains a challenge. The aim of this study is to investigate the radiosensitizing effects of STAT3 inhibitor NSC74859 on ESCC and explore the underlying mechanisms. ECA109 and TE13 cells were exposed to hypoxia, and treated with NSC74859 or radiation, alone or in combination. Cell proliferation, survival, apoptosis, and double-stranded DNA breaks (DSBs) were examined. Nude mice model of ECA109 xenograft was treated with radiation and/or NSC74859. The levels of STAT3, p-STAT3, HIF-1α, and VEGF were detected by Western blot analysis. NSC74859 efficiently radiosensitized ESCC cells and xenografts in nude mice, and inhibited hypoxia-/radiation-induced activation of STAT3 and upregulation of HIF-1α and VEGF expression. NSC74859 confers radiosensitivity in ESCC via the inhibition of STAT3 activation and the downregulation of HIF-1α and VEGF expression. NSC74859 may become a promising radiosensitizer for ESCC radiotherapy.

Topics: Aminosalicylic Acids; Animals; Benzenesulfonates; Blotting, Western; Carcinoma, Squamous Cell; Cell Line, Tumor; Down-Regulation; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Female; Flow Cytometry; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Mice; Mice, Nude; Radiation-Sensitizing Agents; STAT3 Transcription Factor; Xenograft Model Antitumor Assays