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Synthetically Lethal BMN 673 (Talazoparib) Loaded Solid Lipid Nanoparticles for BRCA1 Mutant Triple Negative Breast Cancer

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Abstract

Purpose

The purpose of the study was to produce BMN 673 loaded solid lipid nanoparticles (SLNs) to improve its therapeutic index, to minimize toxicity and to overcome homologous recombination (HR)-mediated resistance.

Methods

Firstly, BMN 673-SLNs were characterized using Nano Zeta Sizer. After treatment with different concentrations of BMN 673 and BMN 673-SLNs, cell viability of HCC1937(BRCA1−/−), HCC1937-R (BMN 673-resistant) TNBC and MCF-10A normal human mammary breast epithelial cell line was analyzed by WST-1 assay. In an attempt to assess the therapeutic synthetic lethality efficacy of SLNs formulation, cell cycle arrest, DNA damage, mRNA expression levels of PARP1, H2AFX, RAD51 and BRCA1 gene were investigated. Then, PARP, ɣH2AX, RAD51 and BRCA1 protein expression and nuclear localization were analyzed by western blot and immunofluorescence analysis.

Results

When compared with BMN 673, BMN 673-SLNs showed remarkably a decrease in HCC1937 and HCC1937-R cells with less damage to MCF-10A cells. BMN 673-SLNs significantly induced toxicity through double-stranded DNA breaks, G2/M cell cycle arrest and PARP cleavage in TNBC cells. Additionally, BMN 673-resistance was mediated by miR-107, miR-193b and miR-1255b targeting BRCA1 and RAD51 in HCC1937 and HCC1937-R cells. However, BMN 673-SLNs treatment could overcome HR-mediated resistance in TNBC cells.

Conclusions

As a result, our findings suggest that SLNs formulation strongly provides a synthetic lethal therapeutic potential in BRCA1 mutated sensitive and resistant TNBC cells.

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Abbreviations

DMEM:

Dulbecco’s modified Eagle’s medium

dsDNA:

Double-strand DNA breaks

FBS:

Fetal bovine serum

GMS:

Glycerol monostearate

HR:

Homologous recombination

SLNs:

Solid lipid nanoparticles

TNBC:

Triple negative breast cancer

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Acknowledgments and Disclosures

We would like to thank Dr.Gokhan Dikmen in Central Research Laboratory, Application and Research Center (ARUM), Eskisehir Osmangazi University, who kindly provided technical support to this study. This study was supported by a grant from the Scientific Research Projects Foundation (BAP) of the Uludag University of Turkey [Project No: BUAP(T)-2015/1]. The authors declare that they have no conflicts of interest. This study represents part of the doctoral dissertation research of Gamze Guney Eskiler completed in the Department of Medical Biology at the University of Uludag.

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Authors and Affiliations

  1. Department of Medical Biology, Faculty of Medicine, Sakarya University, Sakarya, Turkey

    Gamze Guney Eskiler

  2. Department of Medical Biology, Faculty of Medicine, Uludag University, Bursa, Turkey

    Gulsah Cecener, Unal Egeli & Berrin Tunca

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  1. Gamze Guney Eskiler
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  2. Gulsah Cecener
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Correspondence to Gamze Guney Eskiler.

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Guney Eskiler, G., Cecener, G., Egeli, U. et al. Synthetically Lethal BMN 673 (Talazoparib) Loaded Solid Lipid Nanoparticles for BRCA1 Mutant Triple Negative Breast Cancer. Pharm Res 35, 218 (2018). https://doi.org/10.1007/s11095-018-2502-6

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  • DOI: https://doi.org/10.1007/s11095-018-2502-6

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