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The formation of intracellular nanoparticles correlates with cisplatin resistance

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Abstract

Patients treated with the cisplatin often develop strong resistance to the drug after prolonged treatments, ultimately resulting in limited clinical efficacy. One of the possible mechanisms is that the internalized compound may be inactivated before getting access to the nucleus where cisplatin forms a complex with the genomic DNA and triggers a cell death program. However, the nature and intracellular fate of inactivated cisplatin is poorly illustrated. In the present study, we reported for the first time the presence of platinum nanoparticles (Pt-NPs) in the cytoplasm of cells treated with cisplatin. Further analysis also evidenced a correlation of the increased intracellular Pt-NPs formation with cisplatin resistance, and confirmed the process was glutathione S-transferase relevant. Our data suggest that tumor cells may develop cisplatin resistance by converting the drug into less toxic intracellular Pt-NPs, thereby impeding the drug from targeting its substrates.

中文摘要

长期使用顺铂治疗的肿瘤患者容易产生肿瘤细胞耐药性, 影响顺铂的临床治疗效果. 顺铂进入肿瘤细胞后, 在到达靶向细胞 核之前可能会失去活性, 失活后的药物将无法与DNA络合以杀伤细胞, 这是细胞产生药物耐受性的可能机制之一. 然而失活后的顺铂 在细胞内以何种形式存在这一问题尚没有得到完全阐明. 本论文研究发现, 顺铂治疗后的细胞中有铂纳米颗粒存在, 而且该类颗粒的 形成与细胞对顺铂的耐药性有一定的关系. 进一步研究发现细胞内谷胱甘肽转移酶可能在这一机制中起到了重要作用. 数据表明, 细 胞可能通过将高细胞毒性的顺铂转化为低毒性的铂纳米颗粒, 起到阻止顺铂靶向其底物的作用.

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Author information

Authors and Affiliations

  1. State Key Laboratory of Bioelectronics, School of Biological Science & Medical Engineering, Southeast University, Nanjing, 210096, China

    Meng Cao, Fangzhou Liu, Xiquan Zhang, Ziqi Ye, Weiwei Chang, Min Ji & Ning Gu

  2. School of Public Health, Southeast University, Nanjing, 210009, China

    Meng Cao

  3. The Center for Inflammatory and Vascular Diseases, Department of Pathology, University of Maryland School of Medicine Baltimore, Baltimore, MD, 21201, USA

    Fangzhou Liu & Xi Zhan

  4. Department of Head and Neck Surgery, Jiangsu Cancer hospital, Nanjing, 210009, China

    Fangzhou Liu

  5. Nanjing Chia-tai Tianqing Pharmaceutical Co. Ltd, Nanjing, 210038, China

    Xiquan Zhang, Ming Zheng & Weiwei Chang

  6. College of Life and Environmental Science, Wenzhou University, Wenzhou, 325035, China

    Ziqi Ye

Authors
  1. Meng Cao
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  2. Fangzhou Liu
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  3. Xiquan Zhang
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  4. Ming Zheng
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  6. Weiwei Chang
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  7. Min Ji
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  8. Xi Zhan
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  9. Ning Gu
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Corresponding authors

Correspondence to Xi Zhan or Ning Gu.

Additional information

These authors contributed equally to this work.

Meng Cao was born in 1983. He received his PhD degree in biomedical engineering from the School of Biological Science & Medical Engineering, Southeast University, Nanjing, China, in 2013. Currently he is a postdoctoral fellow in Professor Ning Gu’s group. His research interests mainly focus on biochemistry and anti-tumor therapeutics.

Ning Gu was born in 1964. He received his PhD degree in biomedical engineering from the Department of Biomedical Engineering, Southeast University, Nanjing, China, in 1996. Currently he is a Changjiang Scholar Professor and NSFC Outstanding Young Investigator Fund Winner at the School of Biological Science and Medical Engineering, Southeast University. He also serves as the president of Jiangsu Society of Biomedical Engineering, the director of the Research Center for Nanoscale Science and Technology of Southeast University. His research interests include biomaterials, nanobiology, medical imaging, and advanced instrument development.

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Cao, M., Liu, F., Zhang, X. et al. The formation of intracellular nanoparticles correlates with cisplatin resistance. Sci. China Mater. 58, 640–648 (2015). https://doi.org/10.1007/s40843-015-0073-y

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  • DOI: https://doi.org/10.1007/s40843-015-0073-y

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