内源性大麻素系统的调节已被认为是潜在的抗癌策略。在寻找新颖且毒性较小的治疗方案时,内源性大麻素anandamide和油酸合成衍生物的结构修饰,Minerval(HU-600),进行,以获得2-羟基油酸乙醇酰胺(HU-585),它是具有anandamide侧链的HU-600衍生物。我们表明,与HU-600相比,用HU-585处理SK-N-SH神经母细胞瘤细胞可诱导更好的抗肿瘤作用,这通过3-[4,5-二甲基噻唑-2-基]-2,5-二苯基四唑溴化物测定证明,集落形成试验,和迁移测定。此外,如溶酶体β-半乳糖苷酶的活性增加所证明,HU-585表现出促凋亡特性,与HU-600相比,活化的半胱天冬酶-3水平增加和更好的衰老诱导作用。最后,我们观察到HU-585与抗衰老药物ABT-263在体外联合治疗,与单独使用HU-585治疗相比,ABT-737在体内导致增强的抗增殖作用和减少的神经母细胞瘤异种移植物生长。基于这些结果,我们认为HU-585是一种促凋亡和诱导衰老的化合物,比HU-600好.因此,它可能是治疗耐药神经母细胞瘤的有益选择,特别是当与增强其抗肿瘤作用的抗衰老药物联合使用时。
Modulation of the endogenous cannabinoid system has been suggested as a potential anticancer strategy. In the search for novel and less toxic therapeutic options, structural modifications of the endocannabinoid anandamide and the synthetic derivative of oleic acid, Minerval (HU-600), were done to obtain 2-hydroxy oleic acid ethanolamide (HU-585), which is an HU-600 derivative with the anandamide side chain. We showed that treatment of SK-N-SH neuroblastoma cells with HU-585 induced a better anti-tumorigenic effect in comparison to HU-600 as evidenced by 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide assay, colony-forming assay, and migration assay. Moreover, HU-585 demonstrated pro-apoptotic properties shown by increased levels of activated caspase-3 following treatment and a better senescence induction effect in comparison to HU-600, as demonstrated by increased activity of lysosomal β-galactosidase. Finally, we observed that combined treatment of HU-585 with the senolytic drugs ABT-263 in vitro, and ABT-737 in vivo resulted in enhanced anti-proliferative effects and reduced neuroblastoma xenograft growth in comparison to treatment with HU-585 alone. Based on these results, we suggest that HU-585 is a pro-apoptotic and senescence-inducing compound, better than HU-600. Hence, it may be a beneficial option for the treatment of resistant neuroblastoma especially when combined with senolytic drugs that enhance its anti-tumorigenic effects.