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首页> 外文期刊>BMC Cancer >Transcriptomic analysis associated with reversal of cisplatin sensitivity in drug resistant osteosarcoma cells after a drug holiday
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Transcriptomic analysis associated with reversal of cisplatin sensitivity in drug resistant osteosarcoma cells after a drug holiday

机译：毒品假期后耐药性骨肉瘤细胞中顺铂敏感性逆转相关的转录组分析

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BACKGROUND:Resistance to chemotherapy is one of the major hurdles in current cancer therapy. With the increasing occurrence of drug resistance, a paradigm shift in treatment strategy is required. Recently "medication vacation" has emerged as a unique, yet uncomplicated strategy in which withdrawal of drug pressure for certain duration allowed tumor cells to regain sensitivity to the drug. However, little is known about the molecular alterations associated with such an outcome.METHODS:In this study, human osteosarcoma (OS) cells resistant to the extensively used drug cisplatin, were withdrawn from drug pressure, and thereafter cytotoxic response of the cells to the drug was evaluated. We further performed next-generation RNA sequencing and compared transcriptome between parental (OS), resistant (OS-R) and the drug withdrawn (OS-DW) cells. Differentially expressed transcripts were identified, and biological association network (BAN), gene ontology (GO) and pathway enrichment analysis of the differentially regulated transcripts were performed to identify key events associated with withdrawal of drug pressure.RESULTS:Following drug withdrawal, the sensitivity of the cells to the drug was found to be regained. Analysis of the expression profile showed that key genes like, IRAK3, IL6ST, RELA, AKT1, FKBP1A and ADIPOQ went significantly down in OS-DW cells when compared to OS-R. Also, genes involved in Wnt signaling, PI3K-Akt, Notch signaling, and ABC transporters were drastically down-regulated in OS-DW cells compared to OS-R. Although, a very small subset of genes maintained similar expression pattern between OS, OS-R and OS-DW, nonetheless majority of the transcriptomic pattern of OS-DW was distinctively different and unique in comparison to either the drug sensitive OS or drug resistant OS-R cells.CONCLUSION:Our data suggests that though drug withdrawal causes reversal of sensitivity, the transcriptomic pattern does not necessarily show significant match with resistant or parental control cells. We strongly believe that exploration of the molecular basis of drug holiday might facilitate additional potential alternative treatment options for aggressive and resistant cancers.
机译：背景：抗化疗是当前癌症治疗中的主要障碍之一。随着耐药性的不断增加，需要治疗策略的范式转变。最近“药物假期”已成为一种独特而简单的策略，其中持续某些持续时间的药物压力允许肿瘤细胞恢复对药物的敏感性。然而，关于与这种结果相关的分子改变很少。方法：在本研究中，从药物压力下取出对广泛使用的药物顺铂的人骨肉瘤（OS）细胞，然后将细胞的细胞毒性反应从药物压力中取出。评估药物。我们进一步进一步进行了下一代RNA测序并在亲本（OS），抗性（OS-R）和药物中取出（OS-DW）细胞之间的转录组进行比较。鉴定了差异表达的转录物，并进行了生物关联网络（禁令），基因本体学（GO）和差异调节转录物的途径富集分析，以鉴定与药物压力的撤离相关的关键事件。结果：在药物戒断后，敏感性发现药物对药物进行重新获得。与OS-R相比，表达谱的分析表明，伊拉克3，IL6St，Rela，AKT1，FKBP1A和AdipoQ在OS-DW细胞中显着下降。此外，与OS-R相比，WNT信号传导，PI3​​K-AKT，NOTCH信号传导和ABC转运蛋白的基因在OS-DW细胞中急剧下调。尽管，非常小的基因子组在OS，OS-R和OS-DW之间保持相似的表达模式，尽管与药物敏感性OS或耐药性OS相比，OS-DW的大多数转录组模式是明显不同和独特的-R细胞。结论：我们的数据表明，尽管药物戒断导致敏感性的逆转，但转录组模式并不一定表现出与抗性或亲本控制细胞的显着匹配。我们强烈认为，探索药物假期的分子基础可能促进侵略性和抗性癌症的额外潜在的替代治疗方案。

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