Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. Feb 10, 2017; 8(1): 54-66
Published online Feb 10, 2017. doi: 10.5306/wjco.v8.i1.54
Nanoparticle-linked antagonist for leptin signaling inhibition in breast cancer
Tia Harmon, Adriana Harbuzariu, Viola Lanier, Crystal C Lipsey, Ward Kirlin, Lily Yang, Ruben R Gonzalez-Perez
Tia Harmon, Adriana Harbuzariu, Viola Lanier, Crystal C Lipsey, Ward Kirlin, Ruben R Gonzalez-Perez, Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, United States
Lily Yang, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, United States
Author contributions: All authors contributed to this manuscript; Harmon T, Yang L and Gonzalez-Perez RR contributed to the study concept and design; Harbuzariu A, Lanier V, Lipsey CC and Kirlin W contributed to data accumulation, analysis and interpretation.
Supported by The National Cancer Institute at the National Institutes of Health (1R41 CA183399-01A1 to Ruben R Gonzalez-Perez; 5U54 CA118638, S21 MD000101, 5G12 MD0076021, G12 RR026250-03, NIH RR03034 and 1C06 RR18386 to Morehouse School of Medicine); the National Institute of General Medical Sciences, Research Initiative for Scientific Enhancement Program (RISE 5R25 GM058268 to Tia Harmon); and the Congressionally Directed Medical Research Programs-Department of Defense (CDMRP DOD W81XWH-13-1-0382 to Ruben R Gonzalez-Perez).
Informed consent statement: N/A.
Conflict-of-interest statement: The authors of this manuscript indicate that there are no known conflicts of interest.
Data sharing statement: None.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Ruben R Gonzalez-Perez, PhD, Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, 720 Westview Drive, Hugh Gloster Suite 329, Atlanta, GA 30310, United States. rgonzalez@msm.edu
Telephone: +1-404-7521581
Received: August 27, 2016
Peer-review started: August 29, 2016
First decision: November 14, 2016
Revised: December 6, 2016
Accepted: December 27, 2016
Article in press: December 28, 2016
Published online: February 10, 2017
Abstract
AIM

To develop a leptin peptide receptor antagonist linked to nanoparticles and determine its effect on viability of breast cancer cells.

METHODS

The leptin antagonist, LPrA2, was coupled via EDAC [1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide] to iron oxide nanoparticles (IONP-LPrA2) to increase its efficacy. IONP-LPrA2 conjugation was confirmed by Western blot and nanoparticle tracking analysis. Human triple negative breast cancer (TNBC) MDA-MB-231, HCC1806 and estrogen receptor positive (ER+) MCF-7 cells were analyzed for the expression of the leptin receptor, Ob-R. The effects of leptin and antagonist on levels of leptin-induced STAT3 phosphorylation and cyclin D1, cell cycle progression, cell proliferation, and tumorsphere formation in breast cancer cells were determined. Doses of the chemotherapeutics [cisplatin (Cis), cyclophosphamide (CTX), doxorubicin (Dox) and paclitaxel (PTX)] to effectively reduce cell viability were calculated. The effects of combination treatments of IONP-LPrA2 and chemotherapeutics on cell viability were determined.

RESULTS

Western blot analysis of coupling reaction products identified IONP-LPrA2 at approximately 100 kD. IONP-LPrA2 significantly decreased leptin-induced pSTAT3 levels in HCC1806 cells and drastically decreased cyclin D1 levels in all cell lines. IONP-LPrA2 significantly reduced leptin-induced S phase progression and cell proliferation in all breast cancer cell lines and the formation of tumorspheres in MDA-MB-231 cells. Also, IONP-LPrA2 showed an additive effect on the reduction of breast cancer cell survival with chemotherapeutics. Cis plus IONP-LPrA2 produced a significant reduction in the survival of MDA-MB-231 and HCC1806 cells. CTX plus IONP-LPrA2 caused a significant decrease in the survival of MDA-MB-231 cells. Dox plus IONP-LPrA2 caused a marked reduction in the survival of HCC1806 cells. Although, PTX plus IONP-LPrA2 did not have a major effect on the viability of the breast cancer cells when compared to PTX alone.

CONCLUSION

Present data indicate that IONP-LPrA2 may be a useful adjuvant for chemotherapeutic treatment of breast cancer, particularly for TNBC which lacks targeted therapeutic options.

Keywords: Triple negative breast cancer, Obesity, Leptin, Leptin peptide receptor antagonist 2, Iron oxide nanoparticles, Chemotherapy adjuvant

Core tip: Breast cancer is the second leading cause of cancer deaths in women. Triple negative breast cancer is an aggressive subtype that lacks targeted therapy. Obesity is a risk factor for breast cancer and is associated with high leptin levels. Leptin induces the expression of cell cycle associated proteins advancing cell cycle progression. Leptin also increases breast cancer stem cell growth, which promotes chemotherapeutic resistance. We have developed a leptin antagonist linked to iron oxide nanoparticles (IONP-LPrA2) which significantly inhibits leptin-induced cell proliferation and survival of breast cancer cells treated with chemotherapeutics. IONP-LPrA2 can increase chemotherapeutic efficacy in breast cancer.