Agonists of growth hormone-releasing hormone (GHRH) inhibit human experimental cancers in vivo by down-regulating receptors for GHRH

The effects of the growth hormone-releasing hormone (GHRH) agonist MR409 on various human cancer cells were investigated. In H446 small cell lung cancer (SCLC) and HCC827 and H460 (non-SCLC) cells, MR409 promoted cell viability, reduced cell apoptosis, and induced the production of cellular cAMP in vitro. Western blot analyses showed that treatment of cancer cells with MR409 up-regulated the expression of cyclins D1 and D2 and cyclin-dependent kinases 4 and 6, down-regulated p27(kip1), and significantly increased the expression of the pituitary-type GHRH receptor (pGHRH-R) and its splice-variant (SV1). Hence, in vitro MR409 exerts agonistic action on lung cancer cells in contrast to GHRH antagonists. However, in vivo, MR409 inhibited growth of lung cancers xenografted into nude mice. MR409 given s.c. at 5 mu g/day for 4 to 8 weeks significantly suppressed growth of HCC827, H460, and H446 tumors by 48.2%, 48.7%, and 65.6%, respectively. This inhibition of tumor growth by MR409 was accompanied by the down-regulation of the expression of pGHRH-R and SV1 in the pituitary gland and tumors. Tumor inhibitory effects of MR409 in vivo were also observed in other human cancers, including gastric, pancreatic, urothelial, prostatic, mammary, and colorectal. This inhibition of tumor growth parallel to the down-regulation of GHRH-Rs is similar and comparable to the suppression of sex hormone-dependent cancers after the down-regulation of receptors for luteinizing hormone-releasing hormone (LHRH) by LHRH agonists. Further oncological investigations with GHRH agonists are needed to elucidate the underlying mechanisms.