Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
Institute of Physiological Chemistry, University Medical Center Ulm, Ulm, Germany.
Sci Rep. 2018 Apr 3;8(1):5527. doi: 10.1038/s41598-018-23592-z.
Due to the highly invasive nature of Glioblastoma (GB), complete surgical resection is not feasible, while motile tumour cells are often associated with several specific brain structures that enhance treatment-resistance. Here, we investigate the therapeutic potential of Disulfiram and Carbenoxolone, that inhibit two distinct interactions between GB and the brain tissue microenvironment: stress-induced cell-matrix adhesion and gap junction mediated cell-cell communication, respectively. Increase in cell numbers of tumour-initiating cells, which are cultured in suspension as cell clusters, and adherent differentiated cells can be blocked to a similar extent by Carbenoxolone, as both cell populations form gap junctions, but the adherent differentiated cells are much more sensitive to Disulfiram treatment, which - via modulation of NF-κB signalling - interferes with cell-substrate adhesion. Interestingly, inducing adhesion in tumour-initiating cells without differentiating them does not sensitize for Disulfiram. Importantly, combining Disulfiram, Carbenoxolone and the standard chemotherapeutic drug Temozolomide reduces tumour size in an orthotopic mouse model. Isolating GB cells from their direct environment within the brain represents an important addition to current therapeutic approaches. The blockage of cellular interactions via the clinically relevant substances Disulfiram and Carbenoxolone, has distinct effects on different cell populations within a tumour, potentially reducing motility and/or resistance to apoptosis.
由于胶质母细胞瘤（GB）具有高度侵袭性，因此无法进行完全手术切除，而运动性肿瘤细胞通常与几个增强治疗抵抗性的特定大脑结构有关。在这里，我们研究了双硫仑和卡波西醇的治疗潜力，它们分别抑制了 GB 与脑组织微环境之间的两种不同相互作用：应激诱导的细胞-基质黏附和缝隙连接介导的细胞间通讯。在悬浮培养中作为细胞簇培养的肿瘤起始细胞的数量增加，可以通过卡波西醇以相似的程度被阻断，因为这两种细胞群体都形成缝隙连接，但贴壁分化细胞对双硫仑处理更为敏感，后者通过调节 NF-κB 信号干扰细胞-基质黏附。有趣的是，诱导肿瘤起始细胞黏附而不使其分化不会使它们对双硫仑敏感。重要的是，联合使用双硫仑、卡波西醇和标准化疗药物替莫唑胺可减少原位小鼠模型中的肿瘤大小。将 GB 细胞与其在大脑内的直接环境分离，是对当前治疗方法的重要补充。通过临床相关物质双硫仑和卡波西醇阻断细胞相互作用，对肿瘤内的不同细胞群体具有不同的影响，可能降低其运动性和/或抗凋亡能力。
