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
Roberto Perez1,2, Andrew V. Schally1,2,3,4,5,6, Petra Popovics1,2,7,8, Renzhi Cai1,2,3, Wei Sha1,2,4, Ricardo Rincon1,2 and Ferenc G. Rick1,2,9
1 Veterans Affairs Medical Center, Miami, FL
2 South Florida VA Foundation for Research and Education, Miami, FL
3 Department of Pathology, University of Miami, Miller School of Medicine, Miami, FL
4 Division of Hematology/Oncology, University of Miami, Miller School of Medicine, Miami, FL
5 Division of Endocrinology, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL
6 Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL
7 Division of Cardiology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL
8 Department of Medicine III, Technical University Dresden, Dresden, Germany
9 Department of Urology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL
Roberto Perez, email:
Andrew V. Schally, email:
Keywords: triple negative breast cancer, drug resistance, combination therapy, growth-hormone-releasing hormone, antagonist, GHRH analogs
Received: October 12, 2014 Accepted: October 23, 2014 Published: October 24, 2014
Introduction: 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.