Abstract

BackgroundDevelopment of multidrug resistance (MDR) is a major burden of successful chemotherapy, therefore, novel approaches to defeat MDR are imperative. Although the remarkable anti-cancer propensity of silver nanoparticles (AgNP) has been demonstrated and their potential application in MDR cancer has been proposed, the nanoparticle size-dependent cellular events directing P-glycoprotein (Pgp) expression and activity in MDR cancer have never been addressed. Hence, in the present study we examined AgNP size-dependent cellular features in multidrug resistant breast cancer cells.ResultsIn this study we report that 75 nm AgNPs inhibited significantly Pgp efflux activity in drug-resistant breast cancer cells and potentiated the apoptotic effect of doxorubicin, which features were not observed upon 5 nm AgNP treatment. Although both sized AgNPs induced significant ROS production and mitochondrial damage, 5 nm AgNPs were more potent than 75 nm AgNPs in this respect, therefore, these effects can not to be accounted for the reduced transport activity of ATP-driven pumps observed after 75 nm AgNP treatments. Instead we found that 75 nm AgNPs depleted endoplasmic reticulum (ER) calcium stores, caused notable ER stress and decreased plasma membrane positioning of Pgp.ConclusionOur study suggests that AgNPs are potent inhibitors of Pgp function and are promising agents for sensitizing multidrug resistant breast cancers to anticancer drugs. This potency is determined by their size, since 75 nm AgNPs are more efficient than smaller counterparts. This is a highly relevant finding as it renders AgNPs attractive candidates in rational design of therapeutically useful agents for tumor targeting. In the present study we provide evidence that exploitation of ER stress can be a propitious target in defeating multidrug resistance in cancers.

Highlights

  • Development of multidrug resistance (MDR) is a major burden of successful chemotherapy, novel approaches to defeat MDR are imperative

  • Silver nanoparticles induce size‐dependent cytotoxicity in breast cancer cells The successful synthesis of quasi-spherical, citrate-coated silver nanoparticles of approximately 5 nm and 75 nm in diameter was verified by transmission electron microscopy (TEM) and the respective size distributions were assessed by image analysis and by Dynamic Light Scattering (DLS) measurements (Fig. 1a–c)

  • According to TEM micrographs both cells have taken up silver nanoparticles (AgNPs), 5 nm particles were localized in membrane-coated bodies while 75 nm AgNPs were found mainly in the cytoplasm of the cells

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Summary

Introduction

Development of multidrug resistance (MDR) is a major burden of successful chemotherapy, novel approaches to defeat MDR are imperative. In the present study we examined AgNP size-dependent cellular features in multidrug resistant breast cancer cells. Breast cancer is generally considered fairly chemo-responsive, it can attain resistance to a large number of anti-cancer drugs. This multidrugresistant (MDR) phenotype exhibits many distinctive cellular features such as increased tolerance to oxidative stress and apoptosis, activated DNA repair and modulated signal transduction pathways [2, 3], the principal component of MDR is linked to P-glycoprotein (Pgp) overexpression [4, 5]. Significant scientific effort focused on the development of Pgp inhibitors, most of them were dismissed on the grounds of safety, efficacy and disappointing performance in clinical trials [12]

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