Abstract:
This study reports a dose-dependent pro-apoptotic action of synthetic cannabimimetic N-stearoylethanolamine (NSE) on diverse cancer cell lines, including multidrug-resistant models. No antioxidant or cytoprotective effects of NSE were found when it was applied together with doxorubicin. A complex of NSE with the polymeric carrier poly(5-(tert-butylperoxy)-5-methyl-1-hexen-3-yn-co-glycidyl methacrylate)-graft-PEG was synthesized. Co-immobilization of NSE and doxorubicin on this carrier led to a 2-10-fold enhancement of the anticancer activity, particularly, against drug-resistant cells overexpressing ABCC1 and ABCB1. This effect might be caused by accelerated nuclear accumulation of doxorubicin in cancer cells, which led to the activation of the caspase cascade, revealed by Western blot analysis. The NSE-containing polymeric carrier was also able to significantly enhance the therapeutic activity of doxorubicin in mice with implanted NK/Ly lymphoma or L1210 leukemia, leading to the complete eradication of these malignancies. Simultaneously, loading to the carrier prevented doxorubicin-induced elevation of AST and ALT as well as leukopenia in healthy Balb/c mice. Thus, a unique bi-functionality of the novel pharmaceutical formulation of NSE was revealed. It enhanced doxorubicin-induced apoptosis in cancer cells in vitro and promoted its anticancer activity against lymphoma and leukemia models in vivo. Simultaneously, it was very well tolerated preventing frequently observed doxorubicin-associated adverse effects.
摘要:
这项研究报道了合成大麻模拟物N-硬脂酰乙醇胺(NSE)对多种癌细胞系的剂量依赖性促凋亡作用,包括多重耐药模型。当NSE与阿霉素一起施用时,没有发现NSE的抗氧化或细胞保护作用。合成了NSE与聚合物载体聚(5-(叔丁基过氧)-5-甲基-1-己烯-3-炔-共-甲基丙烯酸缩水甘油酯)-接枝-PEG的复合物。NSE和阿霉素在该载体上的共固定导致抗癌活性增强2-10倍,特别是,针对过表达ABCC1和ABCB1的耐药细胞。这种效应可能是由于阿霉素在癌细胞中加速核积累引起的,这导致了胱天蛋白酶级联的激活,通过蛋白质印迹分析显示。含NSE的聚合物载体还能够显着增强阿霉素在患有植入的NK/Ly淋巴瘤或L1210白血病的小鼠中的治疗活性,导致这些恶性肿瘤的完全根除。同时,在健康的Balb/c小鼠中,装载到载体可以防止阿霉素诱导的AST和ALT升高以及白细胞减少。因此,揭示了NSE的新型药物制剂的独特双功能。它在体外增强了多柔比星诱导的癌细胞凋亡,并在体内增强了其对淋巴瘤和白血病模型的抗癌活性。同时,其耐受性非常好,可预防经常观察到的多柔比星相关不良反应.