Nanoparticle-linked antagonist for leptin signaling inhibition in breast cancer  

作　　者：Tia Harmon Adriana Harbuzariu Viola Lanier Crystal C Lipsey Ward Kirlin Lily Yang Ruben R Gonzalez-Perez 

机构地区：[1]Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine [2]Department of Pathology and Laboratory Medicine, Emory University School of Medicine

出　　处：《World Journal of Clinical Oncology》2017年第1期54-66,共13页世界临床肿瘤学杂志（英文版）

基　　金：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);the Congressionally Directed Medical Research Programs-Department of Defense(CDMRP DOD W81XWH-13-1-0382 to Ruben R Gonzalez-Perez)

摘　　要：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.IONPLPrA2 significantly decreased leptin-induced p STAT3 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 usefulAIM 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.IONPLPrA2 significantly decreased leptin-induced p STAT3 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

关 键 词：TRIPLE negative BREAST cancer OBESITY LEPTIN LEPTIN peptide receptor ANTAGONIST 2 Iron oxide nanoparticles Chemotherapy ADJUVANT 

分 类 号：R737.9[医药卫生—肿瘤]