Scriptaid overcomes hypoxia-induced cisplatin resistance in both wild-type and mutant p53 lung cancer cells.
Scriptaid overcomes hypoxia-induced cisplatin resistance in both wild-type and mutant p53 lung cancer cells.
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DOI：
10.18632/oncotarget.12378
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发表时间：
2016-11-01
期刊：
影响因子：
--
通讯作者：
Srivastava T
中科院分区：
文献类型：
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作者：
Pradhan S;Mahajan D;Kaur P;Pandey N;Sharma C;Srivastava T
非小细胞肺癌（NSCLC）占肺癌病例的85%，与化疗/放疗耐药有关。缺氧的肿瘤微环境，其中脉管系统不足导致肿瘤内部的药物渗透率差和次优化疗，这在很大程度上促成了这种耐药性。此外，致瘤细胞的表观遗传变化也改变了它们对不同形式治疗的反应。在我们的研究中，我们研究了顺铂与scriptaid [一种泛组蛋白脱乙酰酶抑制剂（HDACi）]组合在模拟缺氧和亚致死化疗的肿瘤微环境的模型中的有效性。Scriptaid协同增加顺铂在常氧和缺氧中的功效，伴有转移减少和DNA损伤增强。添加scriptaid还克服了在具有稳定的缺氧诱导因子1（HIF 1）-α（突变体）和突变体p53的肺癌细胞中表现出的顺铂耐药性。分子生物学研究表明，联合治疗增加了常氧和缺氧中的凋亡细胞死亡，p38 MAPK具有双重作用。总之，我们的结果表明，低剂量顺铂和斯替米康的组合对NSCLC细胞系具有细胞毒性，可以克服通常与这种癌症相关的缺氧诱导的抗性和突变型p53诱导的不稳定性，并且具有成为有效治疗方式的潜力。
Non-small cell lung cancer (NSCLC), comprising 85% of lung cancer cases, has been associated with resistance to chemo/radiotherapy. The hypoxic tumor micro-environment, where insufficient vasculature results in poor drug penetrance and sub-optimal chemotherapy in the tumor interiors contributes heavily to this resistance. Additionally, epigenetic changes in tumorigenic cells also change their response to different forms of therapy. In our study, we have investigated the effectiveness of a combination of cisplatin with scriptaid [a pan-Histone Deacetylase inhibitor (HDACi)] in a model that mimics the tumor microenvironment of hypoxia and sub-lethal chemotherapy. Scriptaid synergistically increases the efficacy of cisplatin in normoxia as well as hypoxia, accompanied with reduced metastasis and enhanced DNA damage. Addition of scriptaid also overcomes the cisplatin resistance exhibited in lung cancer cells with stabilized hypoxia inducible factor 1 (HIF1)-α (mutant) and mutant p53. Molecular studies showed that the combination treatment increased apoptotic cell death in both normoxia and hypoxia with a dual role of p38MAPK. Together, our results suggest that the combination of low dose cisplatin and scriptaid is cytotoxic to NSCLC lines, can overcome hypoxia induced resistance and mutant p53- induced instability often associated with this cancer, and has the potential to be an effective therapeutic modality.