Abstract
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. 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. 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. 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.
Highlights
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
We have recently reported that the Growth hormone releasing hormone (GHRH) antagonist, MIA-602, suppresses the expression of inflammatory cytokines in human triple negative breast cancer (TNBC) tumors xenografted into nude mice.[36]
We examined the effects of treatment on tumor growth, drug resistance, GHRH receptors (GHRH-R) levels, expression of MDR1 and Nanog, and efflux pump activity
Summary
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. The subtype defined as triple negative breast cancer (TNBC) is negative for estrogen receptor, progesterone receptor, and the human epidermal growth factor receptor 2 (Her2).[2] TNBC accounts for 10-15% of all breast cancer cases and has a higher rate of mortality than other malignancies. The TNBC phenotype is hereditary, affects younger women, is more invasive, and has a much poorer prognosis.[3] These cancers are extremely resistant to the treatment options available for other breast cancers, with drug efflux being the primary mechanism of resistance.[4] This accounts for the low survival rate of women with TNBC.[5] Alternate treatment strategies must be devised to address this clinical deficiency
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