Potential Use of Cetrimonium Bromide as an Apoptosis-Promoting Anticancer Agent for Head and Neck Cancer
Potential Use of Cetrimonium Bromide as an Apoptosis-Promoting Anticancer Agent for Head and Neck Cancer
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DOI：
10.1124/mol.109.055277
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发表时间：
2009-11-01
影响因子：
3.6
通讯作者：
Liu, Fei-Fei
中科院分区：
文献类型：
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作者：
Ito, Emma;Yip, Kenneth W.;Liu, Fei-Fei
通过基于细胞表型驱动的高通量筛选（HTS）2000个生物活性或临床使用的化合物，随后通过体外和体内表征其抗肿瘤功效，鉴定了用于人头颈癌（HNC）的潜在治疗剂西曲溴铵（CTAB）。分别对FaDu（下咽鳞状细胞癌）和GM 05757（原代正常成纤维细胞）进行初步和二次筛选。进一步评估了潜在的命中化合物与标准治疗剂组合对一组正常细胞系和癌细胞系的抗癌特异性和功效。还研究了作用机制、体内抗肿瘤功效和潜在的先导化合物优化。在体外，CTAB与γ射线和顺铂，两个标准的HNC治疗剂的相互作用相加。CTAB对几种HNC细胞系表现出抗癌细胞毒性，对正常成纤维细胞的影响最小;利用癌症特异性代谢畸变的选择性。细胞毒性的中心模式是通过抑制H+-ATP合酶活性和线粒体膜电位去极化，进而与细胞内ATP水平降低、半胱天冬酶激活、sub-G（1）细胞群升高和染色质浓缩相关的细胞凋亡。在体内，CTAB消除了FaDu细胞的肿瘤形成能力，并延迟了已建立肿瘤的生长。因此，使用HTS方法，CTAB被鉴定为具有针对HNC模型的体外和体内功效的潜在致炎性季铵化合物。
A potential therapeutic agent for human head and neck cancer (HNC), cetrimonium bromide (CTAB), was identified through a cell-based phenotype-driven high-throughput screen (HTS) of 2000 biologically active or clinically used compounds, followed by in vitro and in vivo characterization of its antitumor efficacy. The preliminary and secondary screens were performed on FaDu (hypopharyngeal squamous cancer) and GM05757 (primary normal fibroblasts), respectively. Potential hit compounds were further evaluated for their anticancer specificity and efficacy in combination with standard therapeutics on a panel of normal and cancer cell lines. Mechanism of action, in vivo antitumor efficacy, and potential lead compound optimizations were also investigated. In vitro, CTAB interacted additively with gamma radiation and cisplatin, two standard HNC therapeutic agents. CTAB exhibited anticancer cytotoxicity against several HNC cell lines, with minimal effects on normal fibroblasts; a selectivity that exploits cancer-specific metabolic aberrations. The central mode of cytotoxicity was mitochondria-mediated apoptosis via inhibition of H+-ATP synthase activity and mitochondrial membrane potential depolarization, which in turn was associated with reduced intracellular ATP levels, caspase activation, elevated sub-G(1) cell population, and chromatin condensation. In vivo, CTAB ablated tumor-forming capacity of FaDu cells and delayed growth of established tumors. Thus, using an HTS approach, CTAB was identified as a potential apoptogenic quaternary ammonium compound possessing in vitro and in vivo efficacy against HNC models.