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      Reversal of multidrug resistance in human lung cancer cells by delivery of 3-octadecylcarbamoylacrylic acid–cisplatin-based liposomes

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          Abstract

          Liposome-based drug delivery system would be an innovative and promising candidate to circumvent multidrug resistance (MDR) of cisplatin (CDDP). However, the reversal efficacy of liposomal CDDP was severely impaired by weak cellular uptake and insufficient intracellular drug release. In this study, 3-octadecylcarbamoylacrylic acid–CDDP nanocomplex (OMI–CDDP–N)-based liposomes (OCP-L) with high cellular uptake and sufficient intracellular drug release were designed to circumvent MDR of lung cancer. OMI–CDDP–N was synthesized through a pH-sensitive monocarboxylato and an O→Pt coordinate bond, which is more efficient than CDDP. Also, OCP-L incorporated with OMI–CDDP–N could induce effective cellular uptake, enhanced nuclear distribution, and optimal cellular uptake kinetics. In particular, OCP-L presented superior effects on enhancing cell apoptosis and in vitro cytotoxicity in CDDP-resistant human lung cancer (A549/CDDP) cells. The mechanisms of MDR reversal in A549/CDDP cells by OCP-L could attribute to organic cation transporter 2 restoration, ATPase copper-transporting beta polypeptide suppression, hypoxia-inducible factor 1 α-subunit depletion, and phosphatidylinositol 3-kinase/Akt pathway inhibition. These results demonstrated that OCP-L may provide an effective delivery of CDDP to resistant cells to circumvent MDR and enhance the therapeutic index of the chemotherapy.

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          Most cited references 22

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          Defining macropinocytosis.

          Macropinocytosis represents a distinct pathway of endocytosis in mammalian cells. This actin-driven endocytic process is not directly co-ordinated by the presence of cargo but can be induced upon activation of growth factor signalling pathways. The capacity to dissect the contribution of macropinocytosis to cellular processes has been hampered by a lack of unique molecular markers and defining features. While aspects of macropinosome formation and maturation are common to those shared by the other endocytic pathways, a number of key differences have recently begun to emerge and will be discussed in this study. It is now well established that macropinocytosis significantly contributes to antigen presentation by the immune system and is exploited by a range of pathogens for cellular invasion and avoidance of immune surveillance.
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            Subcellular targets of cisplatin cytotoxicity: an integrated view.

            Cisplatin is a chemotherapeutic drug widely used against a variety of cancers. Its clinical utility is severely limited by its toxicity, which mainly affects, but is not limited to, the inner ear and renal tubules. Cisplatin toxicity is determined by target tissue and cell accumulation, subcellular handling and trafficking through diverse subcellular structures, and interaction with macromolecules. Cisplatin accumulates and stresses different organelles from which delay signaling is activated, including mitochondria, lysosomes, the endoplasmic reticulum, the nucleus, the cell membrane and cytoskeleton, and can also be found in the cytosol. This article critically summarizes the available information in order to establish the connection among its known subcellular effects in a hierarchical and integrative framework. Cisplatin causes different types of cell death in a concentration-dependent manner. Knowledge of the events and signaling leading to the different phenotypes is also intertwined within the model, within the scope of the potential utility of this information in the improvement of the pharmacotoxicological profile of this drug. Perspectives for the key aspects that need to be addressed by future investigation are also outlined.
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              Relevance of drug uptake and efflux for cisplatin sensitivity of tumor cells.

              Platinum sensitivity and platinum resistance may involve altered activity of transport proteins. In order to assess the role of drug uptake and efflux in this phenomenon, we compared the expression of three copper transporters, intracellular platinum accumulation, DNA platination and cytotoxicity of cisplatin in two cisplatin-sensitive and -resistant tumor cell line pairs (ovarian A2780/A2780cis and cervical HeLa/HeLaCK cells). Gene expression of importer CTR1, and ATP7A and ATP7B efflux transporters (with and without cisplatin treatment) was investigated using quantitative real-time PCR and platinum concentrations were determined by flameless atomic absorption spectrometry. After incubation with cisplatin, DNA platination was significantly lower in the resistant variants compared to the respective sensitive cell lines, whereas no obvious difference in DNA repair was found. Accordingly, the resistant variants exhibited lower intracellular platinum concentrations than their respective parental cells (2.5- and 2.9-fold lower in A2780cis and HeLaCK cells, respectively). No differences in efflux were observed. Resistant cells expressed lower levels of CTR1 (1.5-1.8-fold) than their sensitive counterparts. Expression differences of ATP7A and ATP7B between resistant and sensitive cells were cell type-specific. The results highlight the relevance of CTR1 for cisplatin sensitivity as there is a clear relationship between lower CTR1 expression, intracellular concentration, DNA platination and cytotoxicity of cisplatin in both resistant cell lines. Our data provide the basis for a quantitative understanding of alterations in uptake and efflux processes leading to cisplatin resistance and might hence facilitate the development of ex vivo assays that can predict cisplatin sensitivity in tumor specimens of patients.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2017
                17 February 2017
                : 11
                : 441-449
                Affiliations
                Department of Pharmaceutics, College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, People’s Republic of China
                Author notes
                Correspondence: Li Yang, Department of Pharmaceutics, College of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, People’s Republic of China, Tel/fax +86 24 2398 6349, Email pharm305@ 123456126.com
                Article
                dddt-11-441
                10.2147/DDDT.S124912
                5322835
                © 2017 Song et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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