Novel nitric oxide donor, nitrated phenylbutyrate, induces cell death of human pancreatic cancer cells and suppresses tumor growth of cancer xenografts
Novel nitric oxide donor, nitrated phenylbutyrate, induces cell death of human pancreatic cancer cells and suppresses tumor growth of cancer xenografts
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DOI：
10.3892/or.2022.8393
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发表时间：
2022-10-01
期刊：
影响因子：
4.2
通讯作者：
Yamasaki, Keishi
中科院分区：
文献类型：
--
作者：
Beppu, Takuro;Nishi, Koji;Yamasaki, Keishi
胰腺癌对化疗的反应率低，这是由于肿瘤周围的低血流导致的低药物转移性。在本研究中，专注于一氧化氮（NO）的血管扩张和抗肿瘤作用，一种新的NO供体，硝化形式的苯丁酸酯（NPB）的合成和对人胰腺癌细胞（AsPC 1和BxPC 3）和异种移植瘤的抗肿瘤作用进行了研究。使用Annexin V，NPB被证实以时间和浓度依赖性方式诱导针对AsPC 1和BxPC 3的细胞死亡。在NPB暴露的细胞中，观察到DAF-FM DA（检测细胞内NO的探针）衍生的荧光。NPB水溶液中亚硝酸盐和硝酸盐的释放非常缓慢，直到溶解后72小时。苯丁酸酯（PB）和羟基PB（其中NPB的硝基被羟基取代）不具有在NPB中观察到的细胞死亡诱导作用。提示NPB的作用依赖于NO的释放。细胞凋亡抑制剂Z-VAD FMK对NPB的细胞死亡诱导作用没有影响，NPB没有显示出明显的caspase-3/7激活。此外，NPB显著降低细胞ATP水平，表明坏死参与了NPB的作用。NPB还特异性地在细胞周期的S期聚集细胞。向具有已建立的BxPC 3异种移植物的小鼠中单剂量的NPB（10 mg/kg）显著抑制肿瘤生长至少7周，而没有明显毒性。本研究的结果表明，NPB有潜力作为一种新的治疗剂的NO为基础的治疗胰腺癌。
Pancreatic cancer has a low response rate to chemotherapy due to the low drug transferability caused by the low blood flow around the tumor. In the present study, focusing on nitric oxide (NO) for its vasodilatory and antitumor effects, a novel NO donor, a nitrated form of phenylbutyrate (NPB) was synthesized and the antitumor effect on human pancreatic cancer cells (AsPC1 and BxPC3) and xenografts was examined. Using Annexin V, NPB was confirmed to induce cell death against AsPC1 and BxPC3 in a time- and concentration-dependent manner. In NPB-exposed cells, DAF-FM DA (a probe to detect intracellular NO) derived fluorescence was observed. Release of nitrite and nitrate from NPB in aqueous solution was very gradual until even 72 h after dissolution. Phenylbutyrate (PB) and hydroxy PB in which the nitro group of NPB was replaced with a hydroxyl group did not have the cell death-inducing effect as observed in NPB. These results suggest that the effect of NPB was dependent on NO release form NPB. Apoptosis inhibitor, Z-VAD FMK, had no effect on the cell death-inducing effect of NPB, and NPB did not show significant activation of caspase-3/7. In addition, NPB significantly decreased cellular ATP levels, suggesting that necrosis is involved in the effect of NPB. NPB also accumulated cells specifically at the S phase of the cell cycle. A single dose of NPB (10 mg/kg) into mice with established BxPC3 xenografts significantly suppressed tumor growth for at least 7 weeks without apparent toxicity. The findings of the present study indicate that NPB has potential as a novel therapeutic agent for NO-based therapy of pancreatic cancer.