Low-dose anti-inflammatory combinatorial therapy reduced cancer stem cell formation in patient-derived preclinical models for tumour relapse prevention
Low-dose anti-inflammatory combinatorial therapy reduced cancer stem cell formation in patient-derived preclinical models for tumour relapse prevention
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DOI：
10.1038/s41416-018-0301-9
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发表时间：
2019-02-19
影响因子：
8.8
通讯作者：
Han, Jongyoon
中科院分区：
文献类型：
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作者：
Khoo, Bee Luan;Grenci, Gianluca;Han, Jongyoon
背景：耐药癌症表型的出现是抗癌治疗的挑战。癌症干细胞被认为是化学耐药性发展的途径之一。方法：我们使用临床前微流体模型对癌细胞系和患者来源的循环肿瘤细胞簇研究了阿霉素和阿司匹林的抗炎组合治疗 (DA)。该模型先前已被证明可以预测患者的总体预后。结果：我们证明低剂量阿司匹林与次优剂量的阿霉素联合使用 72 小时可以产生更高的杀伤功效并增强细胞凋亡。 7天的DA治疗显着降低了癌症干细胞的比例和集落形成能力。 DA 治疗延迟了白细胞介素 6 分泌的抑制，这是由 COX 依赖性和独立途径介导的。由于临床异质性，患者的反应各不相同，DA 治疗后分别有 62.5% 和 64.7% 的样本表现出更高的杀伤功效或癌症干细胞 (CSC) 比例的降低。这些结果凸显了使用源自患者的模型进行药物发现的重要性。结论：这一临床前概念验证旨在减少治疗后压力刺激产生的 CSC 的发生。我们的研究将促进人们更好地了解癌症的抗炎治疗，并降低患者复发的风险。
BACKGROUND: Emergence of drug-resistant cancer phenotypes is a challenge for anti-cancer therapy. Cancer stem cells are identified as one of the ways by which chemoresistance develops.METHOD: We investigated the anti-inflammatory combinatorial treatment (DA) of doxorubicin and aspirin using a preclinical microfluidic model on cancer cell lines and patient-derived circulating tumour cell clusters. The model had been previously demonstrated to predict patient overall prognosis.RESULTS: We demonstrated that low-dose aspirin with a sub-optimal dose of doxorubicin for 72 h could generate higher killing efficacy and enhanced apoptosis. Seven days of DA treatment significantly reduced the proportion of cancer stem cells and colonyforming ability. DA treatment delayed the inhibition of interleukin-6 secretion, which is mediated by both COX-dependent and independent pathways. The response of patients varied due to clinical heterogeneity, with 62.5% and 64.7% of samples demonstrating higher killing efficacy or reduction in cancer stem cell (CSC) proportions after DA treatment, respectively. These results highlight the importance of using patient-derived models for drug discovery.CONCLUSIONS: This preclinical proof of concept seeks to reduce the onset of CSCs generated post treatment by stressful stimuli. Our study will promote a better understanding of anti-inflammatory treatments for cancer and reduce the risk of relapse in patients.