Systemic delivery of lentivirus-mediated secretable TAT-apoptin eradicates hepatocellular carcinoma xenografts in nude mice
Systemic delivery of lentivirus-mediated secretable TAT-apoptin eradicates hepatocellular carcinoma xenografts in nude mice
复制标题
慢病毒介导的分泌型 TAT 凋亡素的全身递送可根除裸鼠中的肝细胞癌异种移植物
DOI：
10.3892/ijo.2012.1547
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发表时间：
2012-09-01
影响因子：
5.2
通讯作者：
Zhu, Qing
中科院分区：
文献类型：
--
作者：
Ma, Jin-Lu;Han, Su-Xia;Zhu, Qing
凋亡素是一种鸡贫血病毒来源的蛋白，已被证明可诱导多种人类癌细胞株的凋亡，但不能诱导正常细胞的凋亡，因此使其成为开发新的治疗策略的候选药物。为了使凋亡素能够有效地转导肿瘤细胞，我们开发了一种新的哺乳动物表达系统，用于体外分泌凋亡素。我们以前已经证明了通过在转录激活因子(TAT)的N端添加分泌信号肽(SP)-凋亡素(SP-TAT-Aoptin)来有效地和肿瘤特异性地杀伤细胞。此外，我们的报告还显示，慢病毒LV-SP-TAT-Aoptin/GFP感染HUVEC细胞后，成功地将高水平的TAT-Aoptin/GFP分泌到培养液中。为了在体内获得持续的凋亡素诱导的肿瘤细胞死亡，我们通过尾静脉注射LV-SP-TAT-Aoptin病毒系统地递送病毒；以表达LV-SP-TAT-GFP的病毒作为阴性对照。值得注意的是，几乎所有的肝细胞癌移植瘤在治疗后都消失了，而接受控制LV-SP-TAT-GFP病毒的移植瘤继续生长。此外，本文介绍的动物实验表明，SP-TAT-凋亡素在体内的毒性很低，证实和推广了体外研究的结果。综上所述，我们的数据有力地表明，系统递送慢病毒介导的可分泌的TAT-Aoptin在体内根除肝癌是可行的。
Apoptin, a chicken anemia virus-derived protein, has been shown to induce apoptosis in various human cancer cell lines, but not in normal cells, thus making it a candidate for the development of novel therapeutic strategies. To enable the efficient transduction of tumor cells with apoptin, we have developed a novel mammalian expression system for the secretion of apoptin in vitro. We have previously shown the efficient and tumor-specific killing of cells by adding a secretory signal peptide (SP) to the N terminus of transacting activator of transcription (TAT)-apoptin (SP-TAT-apoptin). In addition, our report showed the successful secretion of high levels of TAT-apoptin/GFP into the culture medium from HUVEC cells infected by lentivirus LV-SP-TAT-apoptin/GFP. To obtain sustained apoptin-induced tumor cell death in vivo, we injected the LV-SP-TAT-apoptin viruses via the tail vein for systemic delivery of the viruses; viruses expressing LV-SP-TAT-GFP were used as a negative control. Markedly, almost all the hepatocellular carcinoma xenograft tumors disappeared following the treatment while the xenografts that received the control LV-SP-TAT-GFP viruses continued to grow. Moreover, the animal studies presented in this paper demonstrate a low toxicity of SP-TAT-apoptin in vivo, confirming and extending the results of the in vitro studies. Taken together, our data strongly suggest that systemic delivery of lentivirus-mediated secretable TAT-apoptin is feasible to eradicate liver cancer in vivo.