title: Antagonistic analogs of growth hormone-releasing hormone increase the efficacy of treatment of triple negative breast cancer in nude mice with doxorubicin; A preclinical study.
abstract: BACKGROUND
  This study evaluated the effects of an antagonistic analog of growth hormone-releasing hormone, MIA-602, on tumor growth, response to doxorubicin, expression of drug resistance genes, and efflux pump function in human triple negative breast cancers.
  
  
  METHODS
  HCC1806 (doxorubicin-sensitive) and MX-1 (doxorubicin-resistant), cell lines were xenografted into nude mice and treated with MIA-602, doxorubicin, or their combination. Tumors were evaluated for changes in volume and the expression of the drug resistance genes MDR1 and NANOG. In-vitro cell culture assays were used to analyze the effect of MIA-602 on efflux pump function.
  
  
  RESULTS
  Therapy with MIA-602 significantly reduced tumor growth and enhanced the efficacy of doxorubicin in both cell lines. Control HCC1806 tumors grew by 435%, while the volume of tumors treated with MIA-602 enlarged by 172.2% and with doxorubicin by 201.6%. Treatment with the combination of MIA-602 and doxorubicin resulted in an increase in volume of only 76.2%. Control MX-1 tumors grew by 907%, while tumors treated with MIA-602 enlarged by 434.8% and with doxorubicin by 815%. The combination of MIA-602 and doxorubicin reduced the increase in tumor volume to 256%. Treatment with MIA-602 lowered the level of growth hormone-releasing hormone and growth hormone-releasing hormone receptors and significantly reduced the expression of multidrug resistance (MDR1) gene and the drug resistance regulator NANOG. MIA-602 also suppressed efflux pump function in both cell lines.
  
  
  CONCLUSIONS
  We conclude that treatment of triple negative breast cancers with growth hormone-releasing hormone antagonists reduces tumor growth and potentiates the effects of cytotoxic therapy by nullifying drug resistance.
authors.affiliation: Veterans Affairs Medical Center, Miami, FL ; South Florida VA Foundation for Research and Education, Miami, FL.
authors.forename: Roberto
authors.initials: R
authors.lastname: Perez
authors.affiliation: Veterans Affairs Medical Center, Miami, FL ; South Florida VA Foundation for Research and Education, Miami, FL ; Department of Pathology, University of Miami, Miller School of Medicine, Miami, FL ; Division of Hematology/Oncology, University of Miami, Miller School of Medicine, Miami, FL ; Division of Endocrinology, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL ; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Schally
authors.affiliation: Veterans Affairs Medical Center, Miami, FL ; South Florida VA Foundation for Research and Education, Miami, FL ; Division of Cardiology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL ; Department of Medicine III, Technical University Dresden, Dresden, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Popovics
authors.affiliation: Veterans Affairs Medical Center, Miami, FL ; South Florida VA Foundation for Research and Education, Miami, FL ; Department of Pathology, University of Miami, Miller School of Medicine, Miami, FL.
authors.forename: Renzhi
authors.initials: R
authors.lastname: Cai
authors.affiliation: Veterans Affairs Medical Center, Miami, FL ; South Florida VA Foundation for Research and Education, Miami, FL ; Division of Hematology/Oncology, University of Miami, Miller School of Medicine, Miami, FL.
authors.forename: Wei
authors.initials: W
authors.lastname: Sha
authors.affiliation: Veterans Affairs Medical Center, Miami, FL ; South Florida VA Foundation for Research and Education, Miami, FL.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Rincon
authors.affiliation: Veterans Affairs Medical Center, Miami, FL ; South Florida VA Foundation for Research and Education, Miami, FL ; Department of Urology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL.
authors.forename: Ferenc G
authors.initials: FG
authors.lastname: Rick
keywords: GHRH analogs; antagonist; combination therapy; drug resistance; growth-hormone-releasing hormone; triple negative breast cancer