Antitumor effect of combined NAMPT and CD73 inhibition in an ovarian cancer model.
Antitumor effect of combined NAMPT and CD73 inhibition in an ovarian cancer model.
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DOI：
10.18632/oncotarget.6502
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发表时间：
2016-01-19
期刊：
影响因子：
--
通讯作者：
Bruzzone S
中科院分区：
文献类型：
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作者：
Sociali G;Raffaghello L;Magnone M;Zamporlini F;Emionite L;Sturla L;Bianchi G;Vigliarolo T;Nahimana A;Nencioni A;Raffaelli N;Bruzzone S
烟酰胺磷酸核糖转移酶（NAMPT）是细胞内NAD+生物合成的关键酶。NAMPT抑制剂通过消耗NAD+和ATP水平在几种临床前模型中具有强效抗癌活性。最近，我们证明了CD 73能够通过将细胞外NAD+/烟酰胺单核苷酸（NMN）转化为烟酰胺核苷（NR）来利用细胞外NAD +/NMN，NR可以穿过质膜并为人类细胞中的细胞内NAD+生物合成提供燃料。这些过程在本文中通过CD 73或NRK 1特异性沉默证实也发生在人卵巢癌细胞系（OVCAR-3）中。接下来，我们在体内人卵巢癌模型中研究了同时抑制NAMPT（使用FK 866）和CD 73（使用α，β-亚甲基腺苷5′-二磷酸，APCP）的抗肿瘤活性。有趣的是，与单一治疗相比，发现联合治疗显著降低了肿瘤内NAD+、NMN和ATP水平。此外，与单次给药相比，FK 866和APCP联合给药动物腹水渗出液中这些核苷酸的浓度更显著降低。重要的是，FK 866与APCP联合治疗的肿瘤中Ki 67阳性增殖细胞的比例在统计学上显著降低，坏死面积的百分比较高。最后，与单一药物相比，可以证明对联合治疗反应的动物存活率略有但显著增加。我们的研究结果表明，CD 73酶活性的药理学抑制可以被认为是一种手段，以加强NAMPT抑制剂的抗癌作用。
Nicotinamide phosphoribosyltransferase (NAMPT) is a crucial enzyme in the biosynthesis of intracellular NAD+. NAMPT inhibitors have potent anticancer activity in several preclinical models by depleting NAD+ and ATP levels. Recently, we demonstrated that CD73 enables the utilization of extracellular NAD+/nicotinamide mononucleotide (NMN) by converting them to Nicotinamide riboside (NR), which can cross the plasmamembrane and fuel intracellular NAD+ biosynthesis in human cells. These processes are herein confirmed to also occur in a human ovarian carcinoma cell line (OVCAR-3), by means of CD73 or NRK1 specific silencing. Next, we investigated the anti-tumor activity of the simultaneous inhibition of NAMPT (with FK866) and CD73 (with α, β-methylene adenosine 5′-diphosphate, APCP), in an in vivo human ovarian carcinoma model. Interestingly, the combined therapy was found to significantly decrease intratumor NAD+, NMN and ATP levels, compared with single treatments. In addition, the concentration of these nucleotides in ascitic exudates was more remarkably reduced in animals treated with both FK866 and APCP compared with single treatments. Importantly, tumors treated with FK866 in combination with APCP contained a statistically significant lower proportion of Ki67 positive proliferating cells and a higher percentage of necrotic area. Finally, a slight but significant increase in animal survival in response to the combined therapy, compared to the single agents, could be demonstrated. Our results indicate that the pharmacological inhibition of CD73 enzymatic activity could be considered as a means to potentiate the anti-cancer effects of NAMPT inhibitors.