Growth hormone releasing hormone (GHRH) from hypothalamus nominatively stimulates
growth hormone release from adenohypophysis. GHRH is also produced by
cancers, acting as an autocrine/paracrine
growth factor. This
growth factor function is seen in
lymphoma,
melanoma, colorectal, liver, lung, breast, prostate, kidney,
bladder cancers. Pituitary type
GHRH receptors and their splice variants are also expressed in these
malignancies. Synthetic antagonists of the
GHRH receptor inhibit proliferation of
cancers. Besides direct inhibitory effects on
tumors, GHRH antagonists also enhance cytotoxic
chemotherapy. GHRH antagonists potentiate
docetaxel effects on growth of H460
non-small cell lung cancer (NSCLC) and MX-1
breast cancer plus suppressive action of
doxorubicin on MX-1 and HCC1806
breast cancer. We investigated mechanisms of antagonists on
tumor growth, inflammatory signaling,
doxorubicin response, expression of drug resistance genes, and efflux pump function.
Triple negative breast cancer cell xenografted into nude mice were treated with GHRH antagonist,
doxorubicin, or their combination. The combination reduced
tumor growth, inflammatory gene expression, drug-resistance gene expression, cancer stem-cell marker expression, and efflux-pump function. Thus, antagonists increased the efficacy of
doxorubicin in HCC1806 and MX-1
tumors. Growth inhibition of H460 NSCLC by GHRH antagonists induced marked downregulation in expression of prosurvival
proteins K-Ras, COX-2, and pAKT. In HT-29, HCT-116 and HCT-15
colorectal cancer lines, GHRH antagonist treatment caused cellular arrest in S-phase of cell cycle, potentiated inhibition of in vitro proliferation and in vivo growth produced by S-phase specific
cytotoxic agents,
5-FU,
irinotecan and
cisplatin. This enhancement of cytotoxic
therapy by GHRH antagonists should have clinical applications.