4-Nitroquinoline N-oxide is a potent mutagenic and carcinogenic compound that induces DNA damage and oxidative stress, making 4-Nitroquinoline N-oxide an important tool for cancer research and the study of DNA repair mechanisms[1]. 4-Nitroquinoline N-oxide is commonly used to induce cancers such as oral and esophageal cancer in animal models to study tumor development mechanisms and the efficacy of potential cancer therapies[2-3]. 4-Nitroquinoline N-oxide intercalates into DNA, causing oxidative damage and inducing the formation of DNA adducts, which lead to mutations and cancer development[4].
In vitro, treatment of the epidermoid carcinoma cell line KB with 4-Nitroquinoline N-oxide (0.5, 1.0, 2.0µM) significantly induced apoptosis and arrested the cell cycle in the G1 phase. 4-Nitroquinoline N-oxide can cause mitochondrial damage, leading to upregulation of Bax expression and downregulation of Bcl-2[5]. Jurkat T cells and Daudi B cells were treated with 4-Nitroquinoline N-oxide (0.5, 1, 1.5, 2mM) for 48 hours, 4-Nitroquinoline N-oxide significantly reduced the viability of Daudi B cells, increased the expression of the γH2AX protein, induced DNA damage, and promoted apoptosis. However, 4-Nitroquinoline N-oxide had less toxicity towards Jurkat T cells[6].
In vivo, 4-Nitroquinoline N-oxide (100µg/ml) was administered to C57BL/6J mice through drinking water for 8 and 16 weeks to induce esophageal squamous cell carcinoma (ESCC). Mice treated with 4-Nitroquinoline N-oxide for 8 weeks exhibited esophageal epithelial dysplasia, while those treated for 16 weeks developed esophageal cancer. The esophageal lesions induced by 4-Nitroquinoline N-oxide progressed from hyperplasia to dysplasia and eventually to carcinoma[7]. 4-Nitroquinoline N-oxide (100µg/ml) was given to C57BL/6J mice through drinking water for 16 weeks. Senescent cells in the esophagus were detected by bioluminescence imaging in p16+/LUC mice at 14 weeks, primarily in the non-side population (Non-SP) cells. These senescent cells showed significant upregulation of Oncostatin-M (OSM), a cytokine associated with cancer development that can activate oncogenes such as C-MYC. Additionally, the migration of marrow-derived Gfp+ cells into the esophagus was detected in mice treated with 4-Nitroquinoline N-oxide[8].
References:
[1] Bouaoud J, De Souza G, Darido C, et al. The 4-NQO mouse model: An update on a well-established in vivo model of oral carcinogenesis. Methods Cell Biol. 2021;163:197-229.
[2] Li W, Zeng Q, Wang B, et al. Oxidative stress promotes oral carcinogenesis via Thbs1-mediated M1-like tumor-associated macrophages polarization. Redox Biol. 2024 Oct;76:103335.
[3] Sui X, Chen C, Zhou X, et al. Integrative analysis of bulk and single-cell gene expression profiles to identify tumor-associated macrophage-derived CCL18 as a therapeutic target of esophageal squamous cell carcinoma. J Exp Clin Cancer Res. 2023 Feb 27;42(1):51.
[4] Grawish ME, Zyada MM, Zaher AR. Inhibition of 4-NQO-induced F433 rat tongue carcinogenesis by oleuropein-rich extract. Med Oncol. 2011 Dec;28(4):1163-8.
[5] Han H, Pan Q, Zhang B, et al. 4-NQO induces apoptosis via p53-dependent mitochondrial signaling pathway. Toxicology. 2007 Feb 12;230(2-3):151-63.
[6] Sahu SR, Thakur S, Peroumal D, et al. 4-nitroquinoline 1-oxide induces immune cells death to onset early immunosuppression during oral squamous cell carcinoma development. Front Immunol. 2023 Oct 23;14:1274519.
[7] Aziz Z, Washington MK, Jacobse J, et al. A method for scoring 4-nitroquinoline 1-oxide-induced murine esophageal squamous neoplasia. Vet Pathol. 2023 May;60(3):384-393.
[8] Mukherjee A, Epperly MW, Fisher R, et al. Carcinogen 4-Nitroquinoline Oxide (4-NQO) Induces Oncostatin-M (OSM) in Esophageal Cells. In Vivo. 2023 Mar-Apr;37(2):506-518.
4-Nitroquinoline N-oxide是一种强致突变性和致癌性化合物，能够诱导DNA损伤和氧化应激而成为癌症研究和DNA修复机制研究中的重要工具[1]。4-Nitroquinoline N-oxide常用于诱导动物模型中的口腔癌、食管癌等癌症，以研究肿瘤发生机制和潜在癌症治疗的疗效[2-3]。4-Nitroquinoline N-oxide通过嵌入 DNA，引起氧化损伤并诱导 DNA 加合物的形成，从而导致突变和癌症的发生[4]。
在体外，4-Nitroquinoline N-oxide（0.5、1.0、2.0μM）处理表皮样癌细胞系（KB），4-Nitroquinoline N-oxide显著诱导细胞凋亡，并将细胞周期停滞在G（1）期。4-Nitroquinoline N-oxide可对线粒体造成损伤，引起bax表达水平上调和bcl-2下调[5]。4-Nitroquinoline N-oxide（0.5, 1, 1.5, 2mM）处理Jurkat T细胞和Daudi B细胞48小时，4-Nitroquinoline N-oxide显著抑制Daudi B细胞的活性，同时引起细胞中γH2AX蛋白表达水平，诱导DNA损伤，引起细胞凋亡水平增加，但4-Nitroquinoline N-oxide对Jurkat T细胞的毒性较小[6]。
在体内，4-Nitroquinoline N-oxide（100µg/ml）通过饮水给予C57BL/6J小鼠，分别处理8周和16周，用于诱导食管鳞状细胞癌（ESCC）。4-Nitroquinoline N-oxide处理8周的小鼠主要表现为食管上皮的异型增生，而处理16周的小鼠则发展为食管癌。4-Nitroquinoline N-oxide诱导的食管病变从增生进展到异型增生，最终发展为癌[7]。4-Nitroquinoline N-oxide以100µg/ml的浓度通过饮水给予C57BL/6J小鼠，持续16周。4-Nitroquinoline N-oxide处理的小鼠在14周时通过p16+/LUC小鼠的荧光素酶成像检测到食管中的衰老细胞，这些细胞主要位于非侧群（Non-SP）细胞中。4-NQO诱导的衰老细胞表现出Oncostatin-M（OSM）的显著上调，OSM是一种与癌症发生相关的细胞因子，能够激活C-MYC等癌基因。4-Nitroquinoline N-oxide处理的小鼠食管中还检测到骨髓来源的Gfp+细胞的迁移[8]。