冷大气等离子体诱导人胆管癌临床前体内和体外模型中的肿瘤细胞死亡
Cold-atmospheric plasma induces tumor cell death in preclinical in vivo and in vitro models of human cholangiocarcinoma
摘要：
在过去的十年中，冷大气等离子体（CAP）已成为癌症治疗的创新治疗选择。最近，我们已经建立了一种潜在安全的大气压等离子体射流装置，其在胆管癌（CCA）的临床前模型中显示抗肿瘤特性，胆管癌是一种罕见且非常侵袭性的癌症，从胆道系统中出现，几乎没有有效的治疗方法。在本研究中，我们的目的是在体内和体外环境中破译CAP对CCA的抗肿瘤作用的分子机制。在体内，使用皮下异种移植到免疫功能低下的小鼠，CAP治疗CCA诱导的DNA损伤和肿瘤细胞凋亡，分别通过8-氧代鸟嘌呤和切割的半胱天冬酶-3免疫组化进行评价。对肿瘤微环境的分析显示与巨噬细胞极化相关的标志物的变化。在体外，CCA细胞与CAP处理的培养基（即等离子体活化培养基，PAM）孵育导致细胞存活率的剂量反应性降低。在分子水平上，CAP处理诱导双链DNA断裂，随后增加磷酸化和细胞周期主调节因子CHK 1和p53的活化，导致细胞周期停滞和细胞凋亡导致细胞死亡。总之，CAP是一种新的治疗选择，考虑在未来的CCA。
英文摘要：
Through the last decade, cold atmospheric plasma (CAP) has emerged as an innovative therapeutic option for cancer treatment. Recently, we have set up a potentially safe atmospheric pressure plasma jet device that displays antitumoral properties in a preclinical model of cholangiocarcinoma (CCA), a rare and very aggressive cancer emerging from the biliary tree with few efficient treatments. In the present study, we aimed at deciphering the molecular mechanisms underlying the antitumor effects of CAP towards CCA both in an in vivo and in vitro context. In vivo, using subcutaneous xenografts into immunocompromised mice, CAP treatment of CCA induced DNA lesions and tumor cell apoptosis, as evaluated by 8-oxoguanine and cleaved caspase-3 immunohistochemistry, respectively. Analysis of the tumor microenvironment showed changes in markers related to macrophage polarization. In vitro, incubation of CCA cells with CAP-treated culture media (i.e. plasma-activated media, PAM) led to a dose response decrease in cell survival. At molecular level, CAP treatment induced double-strand DNA breaks, followed by an increased phosphorylation and activation of the cell cycle master regulators CHK1 and p53, leading to cell cycle arrest and cell death by apoptosis. In conclusion, CAP is a novel therapeutic option to consider for CCA in the future.
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