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1.
Int J Oncol ; 30(4): 1019-28, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17332943

ABSTRACT

New therapeutic strategies are necessary to improve the treatment of lung cancer. We investigated the effects of bombesin/gastrin-releasing peptide (GRP) antagonist, RC-3940-II, and growth hormone-releasing hormone (GHRH) antagonists, MZ-J-7-114 and MZ-J-7-118, on the expression of epidermal growth factor receptor (EGFR)/HER (-2, -3, and -4) family, angiogenic factors, VEGF-A and VEGF receptors (VEGF-R1 and VEGF-R2), and the apoptotic molecules Bax and Bcl-2, in H-460 and A-549 non-small cell lung carcinomas (NSCLC). Nude mice bearing xenografts of H-460 and A-549 NSCLC were treated daily with these peptide analogues for 4 weeks. The treatment resulted in growth inhibition of H-460 by 22-77% and A-549 NSCLCs by 64-84%. The inhibition of tumor growth was associated with a down-regulation of members of EGFR/HER family. A significant reduction of the levels of expression of EGFR/HER family on both tumors varied from 29-96%: the greatest inhibition being induced by RC-3940-II. Similarly, a significant decrease in the levels of VEGF-A in tumors by 19-60% and VEGF receptors (VEGF-R1, 24-74% and VEGF-R2, 25-50%) was detected after therapy. An up-regulation of Bax by 21-63% and a down-regulation of Bcl-2 by 23-39% was observed only for H-460 NSCLC. Our study demonstrates that human H-460 and A-549 NSCLC, express receptors for GHRH and bombesin/GRP, and respond to the respective antagonists. The antagonists of bombesin/GRP and GHRH could provide a new strategy for treatment of NSCLC through down-regulation of EGFR/HER family and an interference with the angiogenic and apoptotic pathways.


Subject(s)
Bombesin/analogs & derivatives , Bombesin/antagonists & inhibitors , Carcinoma, Non-Small-Cell Lung/drug therapy , Growth Hormone-Releasing Hormone/antagonists & inhibitors , Lung Neoplasms/drug therapy , Neovascularization, Pathologic/drug therapy , Peptide Fragments/therapeutic use , Sermorelin/therapeutic use , Animals , Apoptosis , Bombesin/therapeutic use , Carcinoma, Non-Small-Cell Lung/blood supply , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Line, Tumor , Down-Regulation , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , Humans , Mice , Neovascularization, Pathologic/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Receptors, Bombesin/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-1/metabolism , Xenograft Model Antitumor Assays , bcl-2-Associated X Protein/metabolism
2.
Eur J Cancer ; 41(17): 2735-44, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16291086

ABSTRACT

Bombesin/gastrin-releasing peptide (BN/GRP) antagonists RC-3940-II and RC-3940-Et, and growth hormone-releasing hormone (GHRH) antagonists MZ-J-7-118 and RC-J-29-18 inhibit the growth of human androgen-independent PC-3 and DU-145 prostate cancers in nude mice. Additive inhibitory effects were observed after treatment with both classes of analogs. In the present study, we investigated the effects of these antagonists on intracellular signalling pathways of protein kinase C (PKC), mitogen activated protein kinases (MAPK) and c-fos and c-jun oncogenes that are involved in tumour cell proliferation. In PC-3 tumours, antagonists of BN/GRP and GHRH decreased significantly the expression of PKC isoforms alpha (alpha), eta (eta) and zeta (zeta) and increased that of delta (delta) PKC protein. MAPK was not detectable. In DU-145 tumours, which constitutively express MAPK, all treatments strongly decreased the levels of p42/44 MAPK. Treatment with the antagonists tended to reduce m-RNA for c-jun in both tumour models. In proliferation assays in vitro, inhibitors of PKC and MAPK diminished growth of DU-145 and PC-3 cells. These findings suggest that antagonists of BN/GRP and GHRH inhibit the growth of androgen-independent prostate cancer by affecting intracellular signalling mechanisms of PKC, MAPK and c-jun.


Subject(s)
Bombesin/antagonists & inhibitors , Genes, jun/physiology , Growth Hormone-Releasing Hormone/antagonists & inhibitors , Neoplasm Proteins/antagonists & inhibitors , Prostatic Neoplasms/metabolism , Analysis of Variance , Blotting, Western , Cell Communication , Cell Line, Tumor , Cell Proliferation , Genes, fos/physiology , Humans , Male , Mitogen-Activated Protein Kinases/metabolism , Neoplasm Proteins/metabolism , Prostatic Neoplasms/pathology , Prostatic Neoplasms/prevention & control , Protein Kinase C/metabolism , Reverse Transcriptase Polymerase Chain Reaction
3.
Prostate ; 64(3): 303-15, 2005 Aug 01.
Article in English | MEDLINE | ID: mdl-15754342

ABSTRACT

BACKGROUND: Antagonists of growth hormone releasing hormone (GHRH) as well as antagonists of bombesin/gastrin releasing peptide (BN/GRP) inhibit the growth of various malignancies (cancers) including prostate cancer. METHODS: We investigated the effects of GHRH antagonists MZ-J-7-118 and RC-J-29-18, BN/GRP antagonists RC-3940-II and RC-3940-Et and the combination of MZ-J-7-118 and RC-3940-II on the growth of PC-3 and DU-145 human androgen independent prostate cancers xenografted s.c. into nude mice. To elucidate the mechanisms of action of these analogs, growth factors like IGF-II (insulin-like growth factor-II), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and epidermal growth factor receptor/human epidermal growth factor receptor (EGF-R/HER) family were measured in tumors as well as IGF-I in serum. RESULTS: Antagonists of GHRH and BN/GRP alone or in combination significantly inhibited growth of PC-3 and DU-145 tumors, the greatest inhibition of tumor volume being achieved by combination of MZ-J-7-118 (5 microg/day) and RC-3940-II (10 microg/day). BN/GRP and GHRH antagonists and their combination also decreased the expression of VEGF significantly in PC-3 and non-significantly in DU-145, as measured by radioimmunoassay for VEGF protein and RT-PCR for mRNA levels of VEGF. GHRH and BN/GRP antagonists reduced bFGF concentrations and the maximal binding capacity of EGF receptors, and their mRNA levels in PC-3 and DU-145 tumors. mRNA levels for HER-2 and -3 were also diminished in PC-3 tumors by GHRH and BN/GRP antagonists. No changes in HER-4 were found after treatment. Serum IGF-I and tumoral IGF-II levels were not affected by the analogs. CONCLUSIONS: BN/GRP and GHRH antagonists inhibit growth of PC-3 and DU-145 prostate cancers by suppressing the expression of tumoral growth factors such as VEGF and bFGF as well as the receptors for EGF and related HER-2 and -3. Additive effects on tumor inhibition (TI) in vivo, but not on VEGF, bFGF, or members of the EGF/HER receptor family, can be achieved by the joint administration of both classes of analogs.


Subject(s)
Bombesin/antagonists & inhibitors , ErbB Receptors/genetics , Gastrin-Releasing Peptide/antagonists & inhibitors , Growth Hormone-Releasing Hormone/antagonists & inhibitors , Prostatic Neoplasms/drug therapy , Vascular Endothelial Growth Factor A/genetics , Animals , Bombesin/analogs & derivatives , Bombesin/pharmacology , Cell Division/drug effects , Cell Line, Tumor , Fibroblast Growth Factor 2/genetics , Fibroblast Growth Factor 2/metabolism , Humans , Male , Mice , Mice, Nude , Peptide Fragments/pharmacology , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/physiopathology , RNA, Messenger/analysis , Receptor, ErbB-2/genetics , Receptor, ErbB-3/genetics , Receptor, ErbB-4 , Sermorelin/pharmacology , Vascular Endothelial Growth Factor A/metabolism , Xenograft Model Antitumor Assays
4.
Int J Cancer ; 112(4): 570-6, 2004 Nov 20.
Article in English | MEDLINE | ID: mdl-15382037

ABSTRACT

We investigated the effects of antagonists of growth hormone-releasing hormone (GHRH) alone and in combination with bombesin/gastrin-releasing peptide (BN/GRP) antagonist RC-3940-II on the growth of H-69 human small cell lung carcinoma (SCLC) xenografted into nude mice. Since the activation of the signaling pathways involving protein kinase C (PKC) and the subsequent steps involving mitogen-activated protein kinase (MAPK) and c-fos and c-jun oncogenes are known to be important mechanisms implicated in cellular growth, we investigated how the blockade of tumoral GHRH receptor splice variants and BN/GRP receptors by these antagonists could interfere with these intracellular signaling pathways. Treatment with GHRH antagonists JV-1-65 or MZ-J-7-110 for 4 weeks significantly (p<0.05) decreased the tumor volume by 22.7+/-3.0% and 36.7 +/- 3.6%, respectively, as compared to controls. A larger decrease in tumor volume of 73.0 +/- 9.5% (p<0.01) was produced by BN/GRP antagonist RC-3940-II and its combination with JV-I-65 caused the greatest tumor reduction of 91.0 +/- 9.8% (p<0.01) vs. controls. H-69 SCLC tumors expressed alpha-, betaII-, delta- and eta-PKC isoforms. Antagonists of GHRH and BN/GRP decreased significantly (p<0.05) the expression of betaII- and delta-, but not of alpha- and eta-PKC isoforms. They also inhibited MAPK levels, the effects being significant (p<0.05) in the groups that received BN/GRP antagonist. In addition, expression of c-fos and c-jun mRNA was reduced after combined treatment with JV-1-65 and RC-3940-II. The proliferation of H-69 SCLC cells "in vitro" was also significantly inhibited after incubation of cells with GHRH antagonist, PKC inhibitors or MAPK inhibitor. These findings suggest that the anti-proliferative effects of antagonists of GHRH and BN/GRP on H69-SCLC involve an inhibition of the signaling pathways of specific PKC isoforms, MAPK and c-fos and c-jun oncogenes.


Subject(s)
Bombesin/pharmacology , Carcinoma, Small Cell/physiopathology , Growth Hormone-Releasing Hormone/pharmacology , Lung Neoplasms/physiopathology , Mitogen-Activated Protein Kinase Kinases/pharmacology , Protein Kinase C/antagonists & inhibitors , Protein Kinase C/pharmacology , Animals , Cell Division , Growth Hormone-Releasing Hormone/antagonists & inhibitors , Humans , Mice , Mice, Nude , Proto-Oncogene Proteins c-fos/pharmacology , Proto-Oncogene Proteins c-jun/pharmacology , Signal Transduction , Transplantation, Heterologous
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