Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
Inflammatory Bowel Disease Research Laboratory, Department of Biological Sciences, Institute of Biotechnology, Federal University of Catalão (UFCAT), Catalão, Brazil.
Cancer Sci. 2024 Nov;115(11):3596-3611. doi: 10.1111/cas.16317. Epub 2024 Sep 6.
In the colorectal cancer (CRC) niche, the transcription factors signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB (NF-κB) are hyperactivated in both malignant cells and tumor-infiltrating leukocytes (TILs) and cooperate to maintain cancer cell proliferation/survival and drive protumor inflammation. Through drug repositioning studies, the anthelmintic drug rafoxanide has recently emerged as a potent and selective antitumor molecule for different types of cancer, including CRC. Here, we investigate whether rafoxanide could negatively modulate STAT3/NF-κB and inflammation-associated CRC. The antineoplastic effect of rafoxanide was explored in a murine model of CRC resembling colitis-associated disease. Cell proliferation and/or STAT3/NF-κB activation were evaluated in colon tissues taken from mice with colitis-associated CRC, human CRC cells, and CRC patient-derived explants and organoids after treatment with rafoxanide. The STAT3/NF-κB activation and cytokine production/secretion were assessed in TILs isolated from CRC specimens and treated with rafoxanide. Finally, we investigated the effects of TIL-derived supernatants cultured with or without rafoxanide on CRC cell proliferation and STAT3/NF-κB activation. The results showed that rafoxanide restrains STAT3/NF-κB activation and inflammation-associated colon tumorigenesis in vivo without apparent effects on normal intestinal cells. Rafoxanide markedly reduces STAT3/NF-κB activation in cultured CRC cells, CRC-derived explants/organoids, and TILs. Finally, rafoxanide treatment impairs the ability of TILs to produce protumor cytokines and promote CRC cell proliferation. We report the novel observation that rafoxanide negatively affects STAT3/NF-κB oncogenic activity at multiple levels in the CRC microenvironment. Our data suggest that rafoxanide could potentially be deployed as an anticancer drug in inflammation-associated CRC.
在结直肠癌（CRC）微环境中，转录因子信号转导子和转录激活子 3（STAT3）和核因子-κB（NF-κB）在恶性细胞和肿瘤浸润白细胞（TIL）中均过度激活，并合作维持癌细胞增殖/存活并驱动促肿瘤炎症。通过药物再定位研究，驱虫药拉福替尼最近作为一种针对包括 CRC 在内的不同类型癌症的有效且选择性的抗肿瘤分子出现。在这里，我们研究了拉福替尼是否可以负调控 STAT3/NF-κB 和炎症相关的 CRC。在类似于结肠炎相关疾病的 CRC 的小鼠模型中探索了拉福替尼的抗肿瘤作用。在用拉福替尼处理后，评估了结肠炎相关 CRC 小鼠的结肠组织、人 CRC 细胞和 CRC 患者来源的外植体和类器官中的细胞增殖和/或 STAT3/NF-κB 激活。评估了从 CRC 标本中分离的 TIL 中的 STAT3/NF-κB 激活和细胞因子产生/分泌，并在有或没有拉福替尼培养的情况下对 CRC 细胞增殖和 STAT3/NF-κB 激活进行了研究。结果表明，拉福替尼在体内抑制 STAT3/NF-κB 激活和炎症相关的结肠肿瘤发生，而对正常肠细胞没有明显影响。拉福替尼显著降低了培养的 CRC 细胞、CRC 衍生的外植体/类器官和 TIL 中的 STAT3/NF-κB 激活。最后，拉福替尼治疗损害了 TIL 产生促肿瘤细胞因子和促进 CRC 细胞增殖的能力。我们报告了一个新的观察结果，即拉福替尼在 CRC 微环境中的多个水平上均能负性影响 STAT3/NF-κB 致癌活性。我们的数据表明，拉福替尼可能潜在地被部署为炎症相关 CRC 的抗癌药物。
