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CD123 靶向溶瘤腺病毒在体外和体内抑制急性髓系白血病细胞增殖。

CD123 targeting oncolytic adenoviruses suppress acute myeloid leukemia cell proliferation in vitro and in vivo.

机构信息

College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, Zhejiang, China.

出版信息

Blood Cancer J. 2014 Mar 21;4(3):e194. doi: 10.1038/bcj.2014.15.

DOI:10.1038/bcj.2014.15
PMID:24658372
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3972701/
Abstract

We report here a novel strategy to redirect oncolytic adenoviruses to CD123 by carry a soluble coxsackie-adenovirus receptor (sCAR)-IL3 expression cassette in the viral genome to form Ad.IL3, which sustainably infected acute myeloid leukemia (AML) cells through CD123. Ad.IL3 was further engineered to harbor gene encoding manganese superoxide dismutase (MnSOD) or mannose-binding plant lectin Pinellia pedatisecta agglutinin (PPA), forming Ad.IL3-MnSOD and Ad.IL3-PPA. As compared with Ad.IL3 or Ad.sp-E1A control, Ad.IL3-MnSOD and Ad.IL3-PPA significantly suppressed in vitro proliferation of HL60 and KG-1 cells. Elevated apoptosis was detected in HL60 and KG-1 cells treated with either Ad.IL3-MnSOD or Ad.IL3-PPA. The caspase-9-caspase-7 pathway was determined to be activated by Ad.IL3-MnSOD as well as by Ad.IL3-PPA in HL60 cells. In an HL60/Luc xenograft nonobese diabetic/severe-combined immunodeficiency mice model, Ad.IL3-MnSOD and Ad.IL3-PPA suppressed cancer cell growth as compared with Ad.IL3. A significant difference of cancer cell burden was detected between Ad.IL3 and Ad.IL3-PPA groups at day 9 after treatment. Furthermore, Ad.IL3-MnSOD significantly prolonged mouse survival as compared with Ad.sp-E1A. These findings demonstrated that Ad.IL3-gene could serve as a novel agent for AML therapy. Harboring sCAR-ligand expression cassette in the viral genome may provide a universal method to redirect oncolytic adenoviruses to various membrane receptors on cancer cells resisting serotype 5 adenovirus infection.

摘要

我们在此报告一种新策略，通过在病毒基因组中携带可溶性柯萨奇病毒-腺病毒受体（sCAR）-IL3 表达盒，将溶瘤腺病毒重定向至 CD123，从而形成可持续感染急性髓系白血病（AML）细胞的 Ad.IL3。Ad.IL3 进一步被工程化为携带编码锰超氧化物歧化酶（MnSOD）或甘露糖结合植物凝集素 Pinellia pedatisecta agglutinin（PPA）的基因，形成 Ad.IL3-MnSOD 和 Ad.IL3-PPA。与 Ad.IL3 或 Ad.sp-E1A 对照相比，Ad.IL3-MnSOD 和 Ad.IL3-PPA 显著抑制 HL60 和 KG-1 细胞的体外增殖。在 HL60 和 KG-1 细胞中，在用 Ad.IL3-MnSOD 或 Ad.IL3-PPA 处理时，检测到细胞凋亡增加。在 HL60 细胞中，Ad.IL3-MnSOD 和 Ad.IL3-PPA 激活了 caspase-9-caspase-7 途径。在 HL60/Luc 异种移植非肥胖糖尿病/严重联合免疫缺陷小鼠模型中，与 Ad.IL3 相比，Ad.IL3-MnSOD 和 Ad.IL3-PPA 抑制了癌细胞生长。在治疗后第 9 天，与 Ad.IL3 相比，Ad.IL3 和 Ad.IL3-PPA 组的癌细胞负荷存在显著差异。此外，与 Ad.sp-E1A 相比，Ad.IL3-MnSOD 显著延长了小鼠的存活时间。这些发现表明，Ad.IL3 基因可作为 AML 治疗的新型药物。在病毒基因组中携带 sCAR-配体表达盒可能为将溶瘤腺病毒重定向至癌细胞上的各种膜受体提供一种通用方法，这些受体对血清型 5 腺病毒感染具有抗性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1425/3972701/20d194802913/bcj201415f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1425/3972701/b77d3f338741/bcj201415f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1425/3972701/5b384dc12c56/bcj201415f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1425/3972701/b9683d52c96a/bcj201415f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1425/3972701/20d194802913/bcj201415f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1425/3972701/b77d3f338741/bcj201415f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1425/3972701/5b384dc12c56/bcj201415f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1425/3972701/b9683d52c96a/bcj201415f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1425/3972701/20d194802913/bcj201415f4.jpg

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