A novel transferrin receptor-targeted hybrid peptide disintegrates cancer cell membrane to induce rapid killing of cancer cells.
A novel transferrin receptor-targeted hybrid peptide disintegrates cancer cell membrane to induce rapid killing of cancer cells.
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DOI：
10.1186/1471-2407-11-359
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发表时间：
2011-08-18
期刊：
影响因子：
3.8
通讯作者：
Kawakami K
中科院分区：
文献类型：
--
作者：
Kawamoto M;Horibe T;Kohno M;Kawakami K
转铁蛋白受体(TFR)是一种细胞膜相关糖蛋白，参与细胞对铁的摄取和细胞生长的调节。最近的研究表明，与正常细胞相比，癌细胞上TFR的表达水平升高。这种受体在恶性肿瘤中的表达水平升高，这是一种可获得的细胞外蛋白，可能是治疗癌症的一个有趣的靶点。我们最近设计了一种新型的免疫毒素，称为杂交肽，它是通过化学合成的，由靶向结合肽和含有富阳离子氨基酸成分的裂解肽组成，它可以分解细胞膜，达到杀伤癌细胞的目的。裂解肽是新设计的，由于构象变化，可以诱导癌细胞快速杀伤。在本研究中，我们设计了与这种新型裂解肽相结合的转铁蛋白受体结合肽，并对其体外和体内的细胞毒活性进行了评价。体外实验：我们检测了TFR裂解杂交肽对12种肿瘤细胞株和2种正常细胞系的细胞毒作用。用TFR抗体和siRNA进行竞争试验，证实了TFR的特异性。此外，我们还进行了共聚焦荧光显微镜分析和通过Annexin-V结合、caspase活性和JC-1染色检测细胞凋亡，以评估线粒体膜电位的变化。体内：静脉注射TFR-lytic给有MDA-MB-231细胞的裸鼠模型。3周后取肿瘤切片进行组织学分析。TfR裂解杂交肽对12种肿瘤细胞具有细胞毒活性，IC_(50)低至4.0~9.3μM。正常细胞对该分子不敏感，IC_(50)为50μM。此外，该分子能在10分钟内解离T47D癌细胞的细胞膜，有效地杀死T47D癌细胞，并诱导约80%的细胞凋亡，而对正常细胞则不能。在裸鼠模型中静脉注射TFR裂解肽显著抑制肿瘤进展。TFR裂解肽可能为患者提供一种有效的、选择性的抗癌治疗。
Transferrin receptor (TfR) is a cell membrane-associated glycoprotein involved in the cellular uptake of iron and the regulation of cell growth. Recent studies have shown the elevated expression levels of TfR on cancer cells compared with normal cells. The elevated expression levels of this receptor in malignancies, which is the accessible extracellular protein, can be a fascinating target for the treatment of cancer. We have recently designed novel type of immunotoxin, termed "hybrid peptide", which is chemically synthesized and is composed of target-binding peptide and lytic peptide containing cationic-rich amino acids components that disintegrates the cell membrane for the cancer cell killing. The lytic peptide is newly designed to induce rapid killing of cancer cells due to conformational change. In this study, we designed TfR binding peptide connected with this novel lytic peptide and assessed the cytotoxic activity in vitro and in vivo. In vitro: We assessed the cytotoxicity of TfR-lytic hybrid peptide for 12 cancer and 2 normal cell lines. The specificity for TfR is demonstrated by competitive assay using TfR antibody and siRNA. In addition, we performed analysis of confocal fluorescence microscopy and apoptosis assay by Annexin-V binding, caspase activity, and JC-1 staining to assess the change in mitochondria membrane potential. In vivo: TfR-lytic was administered intravenously in an athymic mice model with MDA-MB-231 cells. After three weeks tumor sections were histologically analyzed. The TfR-lytic hybrid peptide showed cytotoxic activity in 12 cancer cell lines, with IC50 values as low as 4.0-9.3 μM. Normal cells were less sensitive to this molecule, with IC50 values > 50 μM. Competition assay using TfR antibody and knockdown of this receptor by siRNA confirmed the specificity of the TfR-lytic hybrid peptide. In addition, it was revealed that this molecule can disintegrate the cell membrane of T47D cancer cells just in 10 min, to effectively kill these cells and induce approximately 80% apoptotic cell death but not in normal cells. The intravenous administration of TfR-lytic peptide in the athymic mice model significantly inhibited tumor progression. TfR-lytic peptide might provide a potent and selective anticancer therapy for patients.
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DOI：
10.1089/cdd.1987.4.245
发表时间：
1987-01-01
期刊：
CANCER DRUG DELIVERY
影响因子：
--
作者：
HERTLER, AA;SPITLER, LE;FRANKEL, AE
通讯作者：
FRANKEL, AE
影响因子：
82.9
作者：
Chromek, Milan;Slamova, Zuzana;Brauner, Annelie
通讯作者：
Brauner, Annelie
影响因子：
4.8
作者：
Laske, DW;Muraszko, KM;Youle, RJ
通讯作者：
Youle, RJ
影响因子：
20.3
作者：
Moura, IC;Lepelletier, Y;Hermine, O
通讯作者：
Hermine, O
DOI：
10.1073/pnas.162362999
发表时间：
2002-08-06
影响因子：
11.1
作者：
Ng, PP;Dela Cruz, JS;Penichet, ML
通讯作者：
Penichet, ML