Exosome release and low pH belong to a framework of resistance of human melanoma cells to cisplatin.
Exosome release and low pH belong to a framework of resistance of human melanoma cells to cisplatin.
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DOI：
10.1371/journal.pone.0088193
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Fais S
中科院分区：
文献类型：
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作者：
Federici C;Petrucci F;Caimi S;Cesolini A;Logozzi M;Borghi M;D'Ilio S;Lugini L;Violante N;Azzarito T;Majorani C;Brambilla D;Fais S
对细胞毒性药物的内在耐药性是几十年来癌症治疗中的主要问题。微环境酸度是一种简单而高效的耐药性机制，通过损害药物输送来利用。后者通过细胞外质子化和/或螯合到酸性囊泡中来实现。本研究调查了细胞外酸中毒和纳米囊泡（外来体）释放在人肿瘤细胞对顺铂（CisPt）的耐药性中的重要性;与质子泵抑制剂（PPI）干扰这些肿瘤细胞特征的能力平行。结果表明，低pH条件下，人肿瘤细胞对CisPt的摄取明显受损。此外，从这些细胞培养物的上清液中纯化的外来体含有各种量的CisPt，其与培养基的pH条件相关。HPLC-Q-ICP-MS分析显示，从肿瘤细胞培养上清液纯化的外来体含有天然形式的CisPt。PPI预处理增加了细胞摄取的CisPt，与未经处理的细胞相比，在一个酸依赖性的方式。此外，它诱导肿瘤细胞释放外泌体的明显抑制。与单独用CisPt处理的异种移植物的肿瘤相比，从用PPI预处理的异种移植物获得的人肿瘤含有更多的CisPt。进一步的分析显示，体内PPI处理诱导肿瘤来源的外泌体的血浆水平明显降低，所述外泌体也含有较低水平的CisPt。总而言之，这些发现指出了人类恶性黑色素瘤在抵抗可怕的细胞毒素（如顺铂）时的双重机制。这种抗性框架包括低pH依赖性细胞外螯合和外来体介导的消除。这两种机制都受到质子泵抑制的显著损害，导致增加的CisPt依赖性细胞毒性。
Intrinsic resistance to cytotoxic drugs has been a main issue in cancer therapy for decades. Microenvironmental acidity is a simple while highly efficient mechanism of chemoresistance, exploited through impairment of drug delivery. The latter is achieved by extracellular protonation and/or sequestration into acidic vesicles. This study investigates the importance of extracellular acidosis and nanovesicle (exosome) release in the resistance of human tumour cell to cisplatin (CisPt); in parallel to proton pump inhibitors (PPI) ability of interfering with these tumour cell features. The results showed that CisPt uptake by human tumour cells was markedly impaired by low pH conditions. Moreover, exosomes purified from supernatants of these cell cultures contained various amounts of CisPt, which correlated to the pH conditions of the culture medium. HPLC-Q-ICP-MS analysis revealed that exosome purified from tumour cell culture supernatants contained CisPt in its native form. PPI pre-treatment increased cellular uptake of CisPt, as compared to untreated cells, in an acidic-depend manner. Furthermore, it induced a clear inhibition of exosome release by tumour cells. Human tumours obtained from xenografts pretreated with PPI contained more CisPt as compared to tumours from xenografts treated with CisPt alone. Further analysis showed that in vivo PPI treatment induced a clear reduction in the plasmatic levels of tumour-derived exosomes which also contained lower level of CisPt. Altogether, these findings point to the identification of a double mechanism that human malignant melanoma use in resisting to a dreadful cellular poison such as cisplatin. This framework of resistance includes both low pH-dependent extracellular sequestration and an exosome-mediated elimination. Both mechanisms are markedly impaired by proton pump inhibition, leading to an increased CisPt-dependent cytotoxicity.
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影响因子：
3
作者：
Chau, Q;Stewart, DJ
通讯作者：
Stewart, DJ
影响因子：
10.3
作者：
Luciani, F;Spada, M;Fais, S
通讯作者：
Fais, S
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45.3
作者：
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通讯作者：
Kirkwood, JM
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8
作者：
Fan, S.;Niu, Y.;Qin, W.
通讯作者：
Qin, W.
影响因子：
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作者：
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