Barabutis Nektarios, Schally Andrew V
Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, FL 33125, USA.
Proc Natl Acad Sci U S A. 2008 Dec 23;105(51):20470-5. doi: 10.1073/pnas.0811209106. Epub 2008 Dec 15.
Hypothalamic growth hormone-releasing hormone (GHRH) controls the release of growth hormone and acts as a growth factor in various tumors. Potent antagonistic analogues of GHRH have been synthesized that strongly suppress the growth of diverse cancers through several mechanisms. However, the influence of GHRH antagonists on the redox (reduction/oxidation) status of cancers has not been investigated. Cellular generation of reactive oxygen species (ROS) is central to redox signaling and is implicated in the initiation, development, and progression of cancer. In this study, we evaluated by Western blot the effects in vitro of GHRH and its antagonist JMR-132 on proliferating cell nuclear antigen, tumor suppressor protein p53, transcription factor NF-kappaB p50 and its phosphorylated form, caspase 3, and cleaved caspase 3 in the LNCaP human prostate cancer cell line. GHRH stimulated and GHRH antagonist inhibited the expression of the major antioxidant enzymes, as well as the expression of COX 2 and cytochrome c oxidase IV, which are enzymes involved in the generation of ROS. GHRH augmented and GHRH antagonist suppressed lipid and protein oxidative stress markers, as well as the intracellular generation of ROS. In all these tests, GHRH antagonists exerted strong antioxidant activity. Because the metabolism of ROS and oxidative stress have been associated with initiation and progression of not only prostate tumors but also other malignancies, our findings reinforce previous experimental evidence that GHRH antagonists could be useful for cancer therapy.
下丘脑生长激素释放激素（GHRH）控制生长激素的释放，并在多种肿瘤中作为生长因子发挥作用。已合成了强效的GHRH拮抗类似物，它们通过多种机制强烈抑制多种癌症的生长。然而，GHRH拮抗剂对癌症氧化还原（还原/氧化）状态的影响尚未得到研究。细胞活性氧（ROS）生成对于氧化还原信号传导至关重要，并与癌症的发生、发展和进展有关。在本研究中，我们通过蛋白质印迹法评估了GHRH及其拮抗剂JMR-132在体外对LNCaP人前列腺癌细胞系中增殖细胞核抗原、肿瘤抑制蛋白p53、转录因子NF-κB p50及其磷酸化形式、半胱天冬酶3和裂解的半胱天冬酶3的影响。GHRH刺激而GHRH拮抗剂抑制主要抗氧化酶的表达，以及参与ROS生成的COX 2和细胞色素c氧化酶IV的表达。GHRH增强而GHRH拮抗剂抑制脂质和蛋白质氧化应激标志物以及细胞内ROS的生成。在所有这些测试中，GHRH拮抗剂均表现出强大的抗氧化活性。由于ROS代谢和氧化应激不仅与前列腺肿瘤的发生和进展有关，还与其他恶性肿瘤有关，我们的研究结果强化了先前的实验证据，即GHRH拮抗剂可能对癌症治疗有用。
