Fens Marcel H, Cabrales Pedro, Scicinski Jan, Larkin Sandra K, Suh Jung H, Kuypers Frans A, Oronsky Neil, Lybeck Michelle, Oronsky Arnold, Oronsky Bryan
Children's Hospital Oakland Research Institute (CHORI), 5700 M.L.K. Jr Way, Oakland, CA, 94609, USA.
Department of Bioengineering, University of California San Diego (UCSD), 9500 Gilman Dr, La Jolla, CA, 92093, USA.
Med Oncol. 2016 Aug;33(8):85. doi: 10.1007/s12032-016-0798-9. Epub 2016 Jul 4.
This study reveals a novel interaction between deoxyhemoglobin, nitrite and the non-toxic compound, RRx-001, to generate supraphysiologic levels of nitric oxide (NO) in blood. We characterize the nitrite reductase activity of deoxyhemoglobin, which in the presence of bound RRx-001 reduces nitrite at a much faster rate, leading to markedly increased NO generation. These data expand on the paradigm that hemoglobin generates NO via nitrite reduction during hypoxia and ischemia when nitric oxide synthase (NOS) function is limited. Here, we demonstrate that RRx-001 greatly enhances NO generation from nitrite reduction. RRx-001 is thus the first example of a functional superagonist for nitrite reductase. We hypothesize that physiologically this reaction releases the potentially cytotoxic effector NO selectively in hypoxic tumor regions. It may be that a binary NO-H2O2 trigger is indirectly responsible for the observed tumoricidal activity of RRx-001 since NO is known to inhibit mitochondrial respiration.
本研究揭示了脱氧血红蛋白、亚硝酸盐与无毒化合物RRx-001之间的一种新型相互作用，可在血液中产生超生理水平的一氧化氮（NO）。我们对脱氧血红蛋白的亚硝酸盐还原酶活性进行了表征，在结合RRx-001的情况下，脱氧血红蛋白能以更快的速率还原亚硝酸盐，从而导致NO生成显著增加。这些数据拓展了血红蛋白在缺氧和缺血期间（此时一氧化氮合酶（NOS）功能受限）通过亚硝酸盐还原生成NO的范例。在此，我们证明RRx-001极大地增强了亚硝酸盐还原产生的NO。因此，RRx-001是亚硝酸盐还原酶功能性超级激动剂的首个实例。我们推测，在生理状态下，该反应在缺氧肿瘤区域选择性释放具有潜在细胞毒性的效应分子NO。由于已知NO可抑制线粒体呼吸，可能是二元NO-H2O2触发机制间接导致了观察到的RRx-001的杀肿瘤活性。
