Alterations of EGFR/HER, angiogenesis and apoptosis pathways after therapy with antagonists of growth hormone releasing hormone and bombesin in non-small cell lung cancer

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 downregulation of EGFR/HER family and an interference with the angiogenic and apoptotic pathways.

Growth hormone-releasing hormone receptor antagonists inhibit human gastric cancer through downregulation of PAK1–STAT3/NF-κB signaling

“…MZ-5-156 inhibited the release of matrix metalloproteinases, which led to the suppression of invasion in lung cancer (43). In lung cancer and prostate cancer, MZ-J-7-118 and RC-J-29-18 decreased the expression of the EGFR/HER family (44,45). In ovarian cancer, JMR-132 inactivated the EGFR-Akt pathway (46).…”

Growth inhibition of non-small-cell lung carcinoma by BN/GRP antagonist is linked with suppression of K-Ras, COX-2, and pAkt

“…Transactivation of the EGF-R has already been described for BN in head and neck squamous cancer cells (41). It has been shown that BN antagonists downregulate the levels and mRNA expression of EGF-R in SCLC and breast cancer models (10,22), and it was recently found that the inhibition of H-460 and A549 NSCLC tumors by RC-3940-II is associated with a major down-regulation of EGFR as well as HER-2, HER-3, and HER-4 protein levels (42). Thus, negative regulation of RTKs, inhibition of transactivation of the EGF-R, and impaired levels of K-Ras might contribute to the decrease in pAkt levels of Յ85% after treatment with BN/GRP antagonist RC-3940-II, as found in our study.…”

“…Thus, WT p53 is able to mediate repression of the BCL-2 gene and the transactivation of Bax (47). Therefore, up-regulation of WT p53 could be responsible for the increase in the Bax/BCL-2 ratio in xenografts of H460 NSCLC after treatment with BN/GRP antagonist RC-3940-II (42).…”

Targeting gastrin releasing peptide receptors: New options for the therapy and diagnosis of cancer

“…The tumor-inhibitory mechanism of BN/GRP antagonists appears to be more complex than a simple competitive action on the receptor, and is incompletely understood. The main mechanism of tumor inhibitory action of BN/GRP antagonists appears to involve the reduction in levels of members of the Her-family of receptors including EGF-R, Her-2 and Her-3, 34-39 attenuation of oncogene expression including c-fos, c-jun, [40][41][42][43] pAkt, KRAS, COX-2, 44 protein kinases including MAPK 37,45 and PKC isoforms 40,45,46 modulation of wild and mutated form of the tumor suppressor gene p53, 46,47 along with an alteration in BCL-2/BAX ratio 46,47 and inhibition of neovascularisation 48 by affecting growth factors crucial for neoangiogenesis such as VEGF, bFGF and corresponding receptors. 37,47 In a recent study RC-3095 was administered to 25 patients with different advanced malignancies.…”