Anti-inflammatory combinatorial therapy to enhance killing efficacy with patient-derived preclinical models

Jing Zhang, B. L. Khoo
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Abstract

Many chemotherapeutic drugs induce oxidative stress by accelerating the accumulation of reactive oxygen species (ROS), which triggers the death of cancer cells and then causes severe DNA damage in cancer cells. Here, we proposed using a preclinical microfluidic model to evaluate the combination of doxorubicin and aspirin (DA) for anti-inflammatory therapy using patient-derived circulating tumor cell (CTC) clusters. The preclinical model could perform high-throughput screening of drug combinations and used valves to regulate media inflow for CTC cluster formation. We demonstrated that low-dose aspirin (445–500 mg/ml) and a suboptimal dose of doxorubicin (0.5 D) for seven days could produce higher killing efficacy and significantly reduced the proportion of cancer stem cells and colony-forming ability. Compared with the treatment with doxorubicin alone, the intracellular oxidative activity in the sample under combinatorial DA treatment was reduced, as demonstrated by the intensity of Calcein AM. We demonstrated that the treatment outcomes were mediated by the reduction of COX-2, which was associated with inflammation triggered by ROS. Overall, the preclinical model could be used as a proof of concept to demonstrate the efficacy of anti-inflammatory combinatorial therapies by influencing oxidative stress. Similar research could provide a basis for more DNA-related cancer treatment research in the future.
抗炎联合治疗增强患者临床前模型的杀伤效果
许多化疗药物通过加速活性氧(ROS)的积累来诱导氧化应激,从而触发癌细胞的死亡,然后在癌细胞中引起严重的DNA损伤。在这里,我们建议使用临床前微流控模型来评估阿霉素和阿司匹林(DA)联合使用患者源性循环肿瘤细胞(CTC)集群进行抗炎治疗的效果。该临床前模型可以进行高通量药物组合筛选,并使用阀门调节CTC簇形成的介质流入。我们证明,低剂量阿司匹林(445-500 mg/ml)和次优剂量阿霉素(0.5 D)持续7天可以产生更高的杀伤效果,并显著降低癌症干细胞的比例和集落形成能力。与阿霉素单独处理相比,复合DA处理的样品细胞内氧化活性降低,这可以从钙黄蛋白AM的强度看出。我们证明了治疗结果是由COX-2的减少介导的,这与ROS引发的炎症有关。总的来说,临床前模型可以作为一种概念证明,通过影响氧化应激来证明抗炎联合疗法的有效性。类似的研究可以为未来更多与dna相关的癌症治疗研究提供基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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