A novel strategy inducing autophagic cell death in Burkitt's lymphoma cells with anti-CD19-targeted liposomal rapamycin.

A novel strategy inducing autophagic cell death in Burkitt's lymphoma cells with anti-CD19-targeted liposomal rapamycin.
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DOI:
10.1038/bcj.2014.2
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发表时间:
2014-02-07
影响因子:
12.8
通讯作者:
Kato, J.
Kato, J.
中科院分区:
医学1区
文献类型:
--
作者:
Ono, K.;Sato, T.;Iyama, S.;Tatekoshi, A.;Hashimoto, A.;Kamihara, Y.;Horiguchi, H.;Kikuchi, S.;Kawano, Y.;Takada, K.;Hayashi, T.;Miyanishi, K.;Sato, Y.;Takimoto, R.;Kobune, M.;Kato, J.

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复发性或难治性伯基特淋巴瘤通常预后不良,尽管强化化疗诱导淋巴瘤细胞凋亡和/或坏死性死亡。雷帕霉素(Rap)带来自噬,可能是另一种治疗方法。此外,抗CD 19靶向脂质体递送可以使Rap能够特异性地杀死淋巴瘤细胞。将Rap用阴离子脂质体包裹,并与抗CD 19抗体(CD 19-GL-Rap)或抗CD 2抗体(CD 2-GL-Rap)偶联作为对照。荧光探针Cy5.5也以相同的方式脂质体化(CD 19或CD 2-GL-Cy 5.5),以检查抗CD 19靶向脂质体递送到CD 19阳性伯基特淋巴瘤细胞系SKW6.4中的功效。SKW 6. 4细胞对CD 19-GL-Cy 5.5的摄取效果明显优于CD 2-GL-Cy 5.5。当将细胞皮下接种到非肥胖糖尿病/严重联合免疫缺陷小鼠中时,静脉注射CD 19-GL-Cy 5.5使皮下肿瘤发出荧光,而CD 2-GL-Cy 5.5则没有。此外,在体外,CD 19-GL-Rap不仅对SKW6.4细胞而且对来自患者的伯基特淋巴瘤细胞具有比CD 2-GL-Rap更大的杀细胞效果。CD 19-GL-Rap的特异性毒性可被抗CD 19抗体中和。腹腔接种SKW6.4细胞后,静脉注射CD 19-GL-Rap的小鼠存活时间明显长于CD 2-GL-Rap的小鼠。抗CD 19靶向脂质体Rap可能是一种有前途的诱导自噬细胞死亡的淋巴瘤细胞特异性治疗。
Relapsed or refractory Burkitt's lymphoma often has a poor prognosis in spite of intensive chemotherapy that induces apoptotic and/or necrotic death of lymphoma cells. Rapamycin (Rap) brings about autophagy, and could be another treatment. Further, anti-CD19-targeted liposomal delivery may enable Rap to kill lymphoma cells specifically. Rap was encapsulated by anionic liposome and conjugated with anti-CD19 antibody (CD19-GL-Rap) or anti-CD2 antibody (CD2-GL-Rap) as a control. A fluorescent probe Cy5.5 was also liposomized in the same way (CD19 or CD2-GL-Cy5.5) to examine the efficacy of anti-CD19-targeted liposomal delivery into CD19-positive Burkitt's lymphoma cell line, SKW6.4. CD19-GL-Cy5.5 was more effectively uptaken into SKW6.4 cells than CD2-GL-Cy5.5 in vitro. When the cells were inoculated subcutaneously into nonobese diabetic/severe combined immunodeficiency mice, intravenously administered CD19-GL-Cy5.5 made the subcutaneous tumor fluorescent, while CD2-GL-Cy5.5 did not. Further, CD19-GL-Rap had a greater cytocidal effect on not only SKW6.4 cells but also Burkitt's lymphoma cells derived from patients than CD2-GL-Rap in vitro. The specific toxicity of CD19-GL-Rap was cancelled by neutralizing anti-CD19 antibody. The survival period of mice treated with intravenous CD19-GL-Rap was significantly longer than that of mice treated with CD2-GL-Rap after intraperitoneal inoculation of SKW6.4 cells. Anti-CD19-targeted liposomal Rap could be a promising lymphoma cell-specific treatment inducing autophagic cell death.
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