Pancreatic ductal adenocarcinoma (PDAC) is a therapy recalcitrant disease characterized by the aberrations in multiple genes that drive pathogenesis and drug chemoresistance. In this study, we synthesize a library of seven novel nitric oxide-releasing gemcitabine pro-drugs (NO-GEMs) in order to improve the effectiveness of GEM by exploiting the therapeutic effects of NO. Among these NO-GEM pro-drugs we select 5b as the most effective compound in GEM-resistant PDAC cells. After its encapsulation in liposomes for drug delivery the intracellular NO level increases and nitration associated to activity inhibition of the multidrug resistance associated protein 5 (MRP5; ABCC5) occurs. This results in GEM intracellular accumulation and enhanced apoptotic cell death in GEM-resistant PDAC cells, which express MRP5 at higher levels than GEM-sensitive cells. Our results support the development of a new anti-tumoral strategy to efficiently affect GEM-resistant PDAC cells based on the usage of NO-GEM pro-drugs.

胰腺导管腺癌（PDAC）是一种治疗顽固性疾病，其特征在于驱动发病机理和药物耐药性的多个基因中的异常。在这项研究中，我们合成了七个新型的释放一氧化氮的吉西他滨前药（NO-GEMs）库，以通过利用NO的治疗作用来提高GEM的有效性。在这些NO-GEM前药中，我们选择5b在耐GEM的PDAC细胞中是最有效的化合物。将其封装在脂质体中进行药物递送后，细胞内NO水平升高，硝化作用与多药耐药相关蛋白5（MRP5; ABCC5）的活性抑制有关。这会导致GEM耐药PDAC细胞中GEM细胞内积累并增加凋亡细胞死亡，而PDAC细胞表达MRP5的水平高于GEM敏感细胞。我们的研究结果支持开发一种新的抗肿瘤策略，以基于N​​O-GEM前药的使用有效影响GEM耐药PDAC细胞。