Inhibition of PC‐3 human prostate cancers by analogs of growth hormone‐releasing hormone (GH‐RH) endowed with vasoactive intestinal peptide (VIP) antagonistic activity

Abstract

Key words: antagonist of vasoactive intestinal peptide; growth hormone-releasing hormone; androgen-independent prostate cancerAndrogen deprivation is the main treatment for advanced prostatic carcinoma, producing a clinical remission in 70 -80% of cases. Most patients, however, eventually relapse the hormonal therapy and develop androgen-refractory disease. 1 Treatment options available for patients with androgen independent prostate cancer are limited and do not significantly extend the survival time. 2 Consequently, the present methods of treatment of relapsed prostate cancer must be improved. New therapeutic approaches could be developed based on recent advances in the understanding of the role of neuropeptides, neuroendocrine cells and growth factors in the progression of prostate cancer. [3][4][5][6][7][8] Vasoactive intestinal peptide (VIP) and growth hormone-releasing hormone (GH-RH) are members of the family of structurally related regulatory peptides that include also glucagon, secretin, and pituitary adenylate cyclase-activating peptide. 1,9 VIP regulates the growth and function of several normal organs, including the prostate gland. 9,10 Many observations suggest that VIP might be also involved in the neoplastic transformation of prostatic epithelium. VIP-binding sites are found in virtually all specimens of primary and metastatic human prostate cancer. 11 VIP also stimulates the invasiveness of human prostate cancer cell lines, which express mRNA for VIP receptor subtype 1 (VPAC1). 12-14 Thus, it is of interest whether the antagonists of VIP could inhibit growth of malignant prostate, but no in vivo studies in models of human prostate cancer have been reported so far. The use of VIP antagonists has been suggested for the treatment of lung cancer and other malignancies, for which VIP may function as an autocrine growth factor. 15,16 It was also reported that VIP antagonists significantly inhibit the growth of human experimental non-small cell lung cancers (non-SCLC), mammary and pancreatic carcinomas in vitro and in vivo. 16 -19 In view of the involvement of insulin-like growth factor-I (IGF-I) in the progression of various human neoplasms, our laboratory developed antagonistic analogs of GH-RH that inhibit tumor growth by blocking the secretion of growth hormone (GH) from the pituitary gland with resultant decrease in the production of IGF-I in the liver and other organs. 20 We also found that GH-RH antagonists can inhibit the proliferation of diverse cancer cells directly, without the mediation by the pituitary GH/hepatic IGF-I axis. 21,22 GH-RH receptors on tumors that bind GH-RH antagonists and tumoral GH-RH with a high affinity, and that could mediate direct antiproliferative effect of GH-RH antagonists, were recently identified on prostatic and other carcinomas. 21,23,24 Moreover GH-RH antagonists can bind with a lower affinity to the VPAC receptors on membranes of LNCaP human prostate cancers. 22 In superfusion tests GH-RH antagonists show VIP antagonistic effects and inhibit the VIP-induced ...

Endocrine and Antineoplastic Actions of Growth Hormone-Releasing Hormone Antagonists

“…Receptors for VIP and pituitary adenylate cyclase-activating peptide (VPAC-R) show considerable homology with the closely related GHRH receptor and are expressed in prostate, breast, ovarian, endometrial, and several other carcinomas [63,84]. Some antagonists of the JV series, such as JV-1-52, are non-selective VIP/GHRH antagonists and able to block both receptors [85]. This dual effect of the nonselective antagonists could be beneficial for the therapy of cancers expressing both receptors.…”

Diverse Antiapoptotic Signaling Pathways Activated by Vasoactive Intestinal Polypeptide, Epidermal Growth Factor, and Phosphatidylinositol 3-Kinase in Prostate Cancer Cells Converge on BAD

“…GPCR agonists, such as endothelin-1, bombesin, calcitonin, and vasoactive intestinal polypeptide (VIP), have been shown to support androgen-independent growth of prostate cancer cells (26,27). Elevated expression of VIP and VIP receptors has been found in prostate carcinoma, and antagonists of VIP inhibit the growth of prostate cancer xenografts (28,29). VIP is secreted by autonomous nerves in the prostate gland and also can be produced by prostate cancer cells (27, 30 -32).…”

Gene expression of vasoactive intestinal peptide receptors in human lung cancer

“…It was also demonstrated that the VIPhybrid potentiates the cytotoxicity of chemotherapeutic agents in cancer cell lines (15). Vasoactive intestinal peptide/growth hormone-releasing hormone (VIP/ GHRH) antagonists, such as JV-1-52 and JV-1-53 constructed by our group, were also able to inhibit the growth of androgenindependent prostate cancers by abrogating the autocrine/ paracrine mitogenic stimuli of VIP (16). In prostate cancers, a probe specific for a 64 Cu-labeled receptor for PET imaging delineated xenografts and cases of occult prostate carcinoma that were not detectable with 18 F-FDG (17).…”

“…However, it remains to be determined if a radiolabeled VIP analog can be useful for the early detection of lung cancer. The presence of receptors for VIP on human cancers also led to the investigation of specific antagonists of VIP, PACAP and VIP/GHRH for the treatment of lung cancers and other malignancies in which VIP may function as an autocrine growth factor (6,14,16,30). It was reported that VIPhybrid (14) and PG 97-269 selective to VPAC1 receptors (35) could be potential anti-tumor agents.…”

“…JV-1-53 exhibits extremely high VIP antagonistic activity in various biological assays aimed at evaluating its inhibitory effects on the pharmacological actions of VIP, dependent on VPAC1 and VPAC2 receptors (36). It was shown that these and other VIP antagonists significantly inhibited the growth of human experimental NSCLCs, mammary, prostate and pancreatic carcinomas in vitro and in vivo (6,14,16,30,35,36).…”