Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain; Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain.
Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain; Servicio Microbiología, Hospital Universitario Clínico San Cecilio, 18100 Granada, Spain; Ciber de Enfermedades Infecciosas, CiberInfecc, Instituto de Salud Carlos III, 28029 Madrid, Spain.
Biomed Pharmacother. 2023 Jul;163:114760. doi: 10.1016/j.biopha.2023.114760. Epub 2023 Apr 27.
and Purpose: Colorectal cancer (CRC) is one of the cancers with the highest incidence in which APC gene mutations occur in almost 80% of patients. This mutation leads to β-catenin aberrant accumulation and an uncontrolled proliferation. Apoptosis evasion, changes in the immune response and microbiota composition are also events that arise in CRC. Tetracyclines are drugs with proven antibiotic and immunomodulatory properties that have shown cytotoxic activity against different tumor cell lines.
The effect of tigecycline was evaluated in vitro in HCT116 cells and in vivo in a colitis-associated colorectal cancer (CAC) murine model. 5-fluorouracil was assayed as positive control in both studies.
Tigecycline showed an antiproliferative activity targeting the Wnt/β-catenin pathway and downregulating STAT3. Moreover, tigecycline induced apoptosis through extrinsic, intrinsic and endoplasmic reticulum pathways converging on an increase of CASP7 levels. Furthermore, tigecycline modulated the immune response in CAC, reducing the cancer-associated inflammation through downregulation of cytokines expression. Additionally, tigecycline favored the cytotoxic activity of cytotoxic T lymphocytes (CTLs), one of the main immune defenses against tumor cells. Lastly, the antibiotic reestablished the gut dysbiosis in CAC mice increasing the abundance of bacterial genera and species, such as Akkermansia and Parabacteroides distasonis, that act as protectors against tumor development. These findings resulted in a reduction of the number of tumors and an amelioration of the tumorigenesis process in CAC.
Tigecycline exerts a beneficial effect against CRC supporting the use of this antibiotic for the treatment of this disease.
结直肠癌（CRC）是发病率最高的癌症之一，其中 APC 基因突变发生在近 80%的患者中。这种突变导致β-连环蛋白异常积累和不受控制的增殖。细胞凋亡逃避、免疫反应和微生物群落组成的改变也是 CRC 中出现的事件。四环素是一种具有已证实的抗生素和免疫调节特性的药物，已显示出对不同肿瘤细胞系的细胞毒性活性。
在体外的 HCT116 细胞中和体内的结肠炎相关结直肠癌（CAC）小鼠模型中评估替加环素的作用。在这两项研究中，5-氟尿嘧啶被用作阳性对照。
替加环素表现出针对 Wnt/β-连环蛋白途径的增殖活性，并下调 STAT3。此外，替加环素通过外在、内在和内质网途径诱导细胞凋亡，导致 CASP7 水平增加。此外，替加环素调节 CAC 中的免疫反应，通过下调细胞因子表达来减少与癌症相关的炎症。此外，替加环素有利于细胞毒性 T 淋巴细胞（CTLs）的细胞毒性活性，CTLs 是对抗肿瘤细胞的主要免疫防御之一。最后，抗生素使 CAC 小鼠的肠道菌群失调恢复正常，增加 Akkermansia 和 Parabacteroides distasonis 等细菌属和种的丰度，这些细菌属和种可作为预防肿瘤发展的保护因子。这些发现导致肿瘤数量减少，并改善 CAC 的肿瘤发生过程。
替加环素对 CRC 具有有益的作用，支持将这种抗生素用于治疗这种疾病。
