Back to Journals » International Journal of Nanomedicine » Volume 9 » Issue 1

EGFR-targeted plasmonic magnetic nanoparticles suppress lung tumor growth by abrogating G2/M cell-cycle arrest and inducing DNA damage

Authors Kuroda S, Tam J, Roth JA, Sokolov K, Ramesh R

Received 11 April 2014

Accepted for publication 8 May 2014

Published 8 August 2014 Volume 2014:9(1) Pages 3825—3839

DOI https://doi.org/10.2147/IJN.S65990

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Shinji Kuroda,1 Justina Tam,2 Jack A Roth,1 Konstantin Sokolov,2 Rajagopal Ramesh3–5

1Department of Thoracic and Cardiovascular Surgery, 2Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3Department of Pathology, 4Graduate Program in Biomedical Sciences, 5Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

Background: We have previously demonstrated the epidermal growth factor receptor (EGFR)-targeted hybrid plasmonic magnetic nanoparticles (225-NP) produce a therapeutic effect in human lung cancer cell lines in vitro. In the present study, we investigated the molecular mechanism of 225-NP-mediated antitumor activity both in vitro and in vivo using the EGFR-mutant HCC827 cell line.
Methods: The growth inhibitory effect of 225-NP on lung tumor cells was determined by cell viability and cell-cycle analysis. Protein expression related to autophagy, apoptosis, and DNA-damage were determined by Western blotting and immunofluorescence. An in vivo efficacy study was conducted using a human lung tumor xenograft mouse model.
Results: The 225-NP treatment markedly reduced tumor cell viability at 72 hours compared with the cell viability in control treatment groups. Cell-cycle analysis showed the percentage of cells in the G2/M phase was reduced when treated with 225-NP, with a concomitant increase in the number of cells in Sub-G1 phase, indicative of cell death. Western blotting showed LC3B and PARP cleavage, indicating 225-NP-treatment activated both autophagy- and apoptosis-mediated cell death. The 225-NP strongly induced γH2AX and phosphorylated histone H3, markers indicative of DNA damage and mitosis, respectively. Additionally, significant γH2AX foci formation was observed in 225-NP-treated cells compared with control treatment groups, suggesting 225-NP induced cell death by triggering DNA damage. The 225-NP-mediated DNA damage involved abrogation of the G2/M checkpoint by inhibiting BRCA1, Chk1, and phospho-Cdc2/CDK1 protein expression. In vivo therapy studies showed 225-NP treatment reduced EGFR phosphorylation, increased γH2AX foci, and induced tumor cell apoptosis, resulting in suppression of tumor growth.
Conclusion: The 225-NP treatment induces DNA damage and abrogates G2/M phase of the cell cycle, leading to cellular apoptosis and suppression of lung tumor growth both in vitro and in vivo. Our findings provide a rationale for combining 225-NP with other DNA-damaging agents for achieving enhanced anticancer activity.

Keywords: lung cancer, epidermal growth factor receptor, autophagy

Creative Commons License 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. 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. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

Download Article [PDF]  View Full Text [HTML][Machine readable]

 

Other articles by this author:

Tumor-targeted and pH-controlled delivery of doxorubicin using gold nanorods for lung cancer therapy

Amreddy N, Muralidharan R, Babu A, Mehta M, Johnson EV, Zhao YD, Munshi A, Ramesh R

International Journal of Nanomedicine 2015, 10:6773-6788

Published Date: 29 October 2015

Drug resistance in lung cancer

Manish Shanker, David Willcutts, Jack A Roth, et al

Lung Cancer: Targets and Therapy 2010, 1:23-36

Published Date: 13 May 2010

Readers of this article also read:

Tumor-targeted and pH-controlled delivery of doxorubicin using gold nanorods for lung cancer therapy

Amreddy N, Muralidharan R, Babu A, Mehta M, Johnson EV, Zhao YD, Munshi A, Ramesh R

International Journal of Nanomedicine 2015, 10:6773-6788

Published Date: 29 October 2015

Molecular targets in arthritis and recent trends in nanotherapy

Roy K, Kanwar RK, Kanwar JR

International Journal of Nanomedicine 2015, 10:5407-5420

Published Date: 26 August 2015

Antileukemic effect of zerumbone-loaded nanostructured lipid carrier in WEHI-3B cell-induced murine leukemia model

Rahman HS, Rasedee A, How CW, Zeenathul NA, Chartrand MS, Yeap SK, Abdul AB, Tan SW, Othman HH, Ajdari Z, Namvar F, Arulselvan P, Fakurazi S, Mehrbod P, Daneshvar N, Begum H

International Journal of Nanomedicine 2015, 10:1649-1666

Published Date: 2 March 2015

Nanoparticle delivery of an AKT/PDK1 inhibitor improves the therapeutic effect in pancreatic cancer

Lucero-Acuña A, Jeffery JJ, Abril ER, Nagle RB, Guzman R, Pagel MD, Meuillet EJ

International Journal of Nanomedicine 2014, 9:5653-5665

Published Date: 3 December 2014

Enhanced antidepressant-like effects of the macromolecule trefoil factor 3 by loading into negatively charged liposomes

Qin J, Yang X, Mi J, Wang J, Hou J, Shen T, Li Y, Wang B, Li X, Zhu W

International Journal of Nanomedicine 2014, 9:5247-5257

Published Date: 12 November 2014

Determination of factors controlling the particle size and entrapment efficiency of noscapine in PEG/PLA nanoparticles using artificial neural networks

Shalaby KS, Soliman ME, Casettari L, Bonacucina G, Cespi M, Palmieri GF, Sammour OA, El Shamy AA

International Journal of Nanomedicine 2014, 9:4953-4964

Published Date: 23 October 2014

Nanotechnology-based drug delivery systems for treatment of oral cancer: a review

Calixto G, Bernegossi J, Fonseca-Santos B, Chorilli M

International Journal of Nanomedicine 2014, 9:3719-3735

Published Date: 8 August 2014

Applications of nanotechnology for melanoma treatment, diagnosis, and theranostics

Chen J, Shao R, Zhang XD, Chen C

International Journal of Nanomedicine 2013, 8:2677-2688

Published Date: 24 July 2013

Crystallization after intravitreal ganciclovir injection

Pitipol Choopong, Nattaporn Tesavibul, Nattawut Rodanant

Clinical Ophthalmology 2010, 4:709-711

Published Date: 14 July 2010