STAT3, a transcriptional mediator of oncogenic signaling, is constitutively active in ~70% of human cancers. The development of STAT3 inhibitors remains an active area of research as no inhibitors have yet to be approved for the treatment of human cancer. Herein, we revealed that bruceantinol (BOL) is a novel STAT3 inhibitor demonstrating potent antitumor activity in in vitro and in vivo human colorectal cancer (CRC) models. BOL strongly inhibited STAT3 DNA-binding ability (IC₅₀ = 2.4 pM), blocked the constitutive and IL-6-induced STAT3 activation in a dose- and time-dependent manner, and suppressed transcription of STAT3 target genes encoding anti-apoptosis factors (MCL-1, PTTG1, and survivin) and cell-cycle regulators (c-Myc). Structure-activity relationship studies demonstrated that the C15 side chain on BOL affected its ability to bind STAT3. Administration of 4 mg/kg BOL significantly inhibited CRC tumor xenografts [p < 0.001], but no effect was observed in a STAT3^-/- tumor model. Additional studies showed that BOL effectively sensitized MEK inhibitors through repression of p-STAT3 and MCL-1 induction, known resistance mechanisms of MEK inhibition. Taken together, our findings suggest BOL is a novel therapeutic STAT3 inhibitor that can be used either alone or in combination with MEK inhibitors for the treatment of human CRC.

中文翻译：

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用新型STAT3抑制剂Bruceantinol靶向结肠癌。

STAT3是致癌信号的转录介质，在约70％的人类癌症中具有组成型活性。STAT3抑制剂的开发仍然是一个活跃的研究领域，因为尚无任何抑制剂被批准用于治疗人类癌症。在本文中，我们揭示了bruceantinol（BOL）是一种新型STAT3抑制剂，在体外和体内人结肠直肠癌（CRC）模型中均显示出强大的抗肿瘤活性。BOL强烈抑制STAT3 DNA结合能力（IC ₅₀ = 2.4 pM），以剂量和时间依赖性方式阻断组成型和IL-6诱导的STAT3激活，并抑制编码抗凋亡因子（MCL-1，PTTG1和survivin）和细胞的STAT3目标基因的转录循环调节器（c-Myc）。结构-活性关系研究表明，BOL上的C15侧链影响了其与STAT3结合的能力。给予4 mg / kg BOL可显着抑制CRC肿瘤异种移植[p <0.001]，但在STAT3 ^-/-中未观察到作用肿瘤模型。其他研究表明，BOL通过抑制p-STAT3和MCL-1诱导（已知的MEK抑制耐药机制）有效地使MEK抑制剂致敏。综上所述，我们的发现表明BOL是一种新型的STAT3治疗性抑制剂，可单独使用或与MEK抑制剂联合用于治疗人CRC。