Antitumor effect of gemcitabine-loaded albumin nanoparticle on gemcitabine-resistant pancreatic cancer induced by low hENT1 expression.
Antitumor effect of gemcitabine-loaded albumin nanoparticle on gemcitabine-resistant pancreatic cancer induced by low hENT1 expression.
复制标题
吉西他滨白蛋白纳米粒对hENT1低表达诱导的吉西他滨耐药胰腺癌的抗肿瘤作用
DOI：
10.2147/ijn.s166769
复制
发表时间：
2018
影响因子：
8
通讯作者：
Jin C
中科院分区：
文献类型：
--
作者：
Guo Z;Wang F;Di Y;Yao L;Yu X;Fu D;Li J;Jin C
目的吉西他滨是目前治疗胰腺癌的标准一线化疗药物。然而，许多因素可能导致吉西他滨耐药。其中一个重要原因是hENT 1的低表达。在这项研究中，我们测试了吉西他滨负载人血清白蛋白纳米粒（GEM-HSA-NP）对hENT 1低表达诱导的吉西他滨耐药胰腺癌的抗肿瘤作用。材料和方法利用S-（4-硝基苄基）-6-硫代肌苷抑制hENT 1的活性并模拟低hENT 1表达。对人胰腺癌细胞系如BxPC-3和SW 1990进行生长抑制测定和细胞周期和凋亡分析。使用患者来源的异种移植物（PDX）模型研究体内抗肿瘤作用。对健康昆明种小鼠进行体内毒性评价。结果在体外实验中，当肿瘤细胞对吉西他滨耐药时，GEM-HSA-NP可抑制肿瘤细胞增殖，阻滞细胞周期，诱导肿瘤细胞凋亡。在体内研究中，GEM-HSA-NP比吉西他滨更有效地抑制肿瘤生长，无论PDX模型中hENT 1的表达水平是高还是低。体内毒性评价表明，与吉西他滨相比，GEM-HSA-NP的生物毒性没有增加。结论GEM-HSA-NP能克服hENT 1低表达诱导的吉西他滨耐药，具有潜在的临床应用价值。
Purpose Gemcitabine is currently the standard first-line chemotherapeutic drug for treating pancreatic cancer. However, many factors can contribute to gemcitabine resistance. One of the most important reasons is the low hENT1 expression. In this study, we tested the antitumor effect of gemcitabine-loaded human serum albumin nanoparticle (GEM-HSA-NP) on gemcitabine-resistant pancreatic cancer induced by low hENT1 expression. Materials and methods S-(4-nitrobenzyl)-6-thioinosine was utilized to inhibit the activity of hENT1 and simulate low hENT1 expression. Growth inhibition assays and cell cycle and apoptosis analyses were performed on human pancreatic cancer cell lines such as BxPC-3 and SW1990. The in vivo antitumor effect was studied by using patient-derived xenograft (PDX) models. The in vivo toxicity assessment was performed on healthy Kunming mice. Results In in vitro studies, GEM-HSA-NP showed its ability to inhibit cell proliferation, arrest cell cycle and induce apoptosis when tumor cells were resistant to gemcitabine. In in vivo studies, GEM-HSA-NP was more effective than gemcitabine on inhibiting tumor growth whether the expression levels of hENT1 were high or low in PDX models. The in vivo toxicity assessment showed that the biotoxicity of GEM-HSA-NP did not increase compared with gemcitabine. Conclusion GEM-HSA-NP can overcome gemcitabine resistance induced by low hENT1 expression, which suggests its potential role for the clinical application.