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.
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.
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DOI：
10.3892/ijo.30.4.1019
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发表时间：
2007-04
影响因子：
5.2
通讯作者：
C. A. Kanashiro;A. Schally;M. Zarándi;Brian D Hammann;J. Varga
中科院分区：
文献类型：
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作者：
C. A. Kanashiro;A. Schally;M. Zarándi;Brian D Hammann;J. Varga
需要新的治疗策略来改善肺癌的治疗。我们研究了铃蟾肽/胃泌素释放肽（GRP）拮抗剂RC-3940-II和生长激素释放激素（GHRH）拮抗剂MZ-J-7-114和MZ-J-7-118对表皮生长因子受体（EGFR）/HER（-2、-3和-4）家族、血管生成因子、 H-460 和 A-549 非小细胞肺癌 (NSCLC) 中的 VEGF-A 和 VEGF 受体（VEGF-R1 和 VEGF-R2）以及凋亡分子 Bax 和 Bcl-2。每天用这些肽类似物治疗携带 H-460 和 A-549 NSCLC 异种移植物的裸鼠，持续 4 周。该治疗导致 H-460 NSCLC 生长抑制 22-77%，A-549 NSCLC 生长抑制 64-84%。肿瘤生长的抑制与 EGFR/HER 家族成员的下调有关。两种肿瘤上 EGFR/HER 家族表达水平显着降低 29-96%：RC-3940-II 诱导的最大抑制。同样，治疗后检测到肿瘤中 VEGF-A 水平显着下降 19-60%，VEGF 受体（VEGF-R1，24-74%，VEGF-R2，25-50%）水平显着下降。仅在 H-460 NSCLC 中观察到 Bax 上调 21-63%，Bcl-2 下调 23-39%。我们的研究表明，人类 H-460 和 A-549 NSCLC 表达 GHRH 和铃蟾肽/GRP 受体，并对各自的拮抗剂产生反应。铃蟾肽/GRP 和 GHRH 拮抗剂可以通过下调 EGFR/HER 家族并干扰血管生成和细胞凋亡途径，为 NSCLC 的治疗提供新策略。
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.