Department of Immunology, Molecular Medicine Group, the Norwegian Radium Hospital, Institute for Cancer Research Montebello, N-0310, Oslo, Norway.
Biochem Pharmacol. 2012 Nov 1;84(9):1123-32. doi: 10.1016/j.bcp.2012.08.002. Epub 2012 Aug 14.
Antimicrobial peptides selectively kill bacteria while maintaining low mammalian cell cytotoxicity. However, they become cytotoxic subsequent to internalization. Here we have conjugated the lytic peptide (KLAKLAK)(2) to either a cancer-cell binding peptide (LTVSPWY) selected from peptide libraries or to a gastrin-releasing peptide (GNHWAVGHLM) in order to direct the lytic peptide to cancer cells. Peptide cytotoxicity was tested in breast MCF-7 and MDA-MB-231 cancer cells. The fusion peptides were internalized by cancer cells, disintegrated the cell membrane and induced rapid killing of the cells with IC50 values as low as 4-7 μM. Peptide cytotoxicity was dependent on the targeting receptor. Indeed, addition of free targeting peptide reduced cell killing. Blood lymphocytes and normal human mammary epithelial cells were less sensitive to the fusion peptides. Although most of the cells were killed by necrosis, fusion peptides branched with DNA oligonucleotides induced apoptosis as assayed by annexin V staining and activation of caspase 3. Therefore, the new designed drug peptides might provide a potent and selective anticancer therapy.
抗菌肽选择性地杀死细菌，同时保持低哺乳动物细胞细胞毒性。然而，它们在被内化后会变得具有细胞毒性。在这里，我们将裂解肽（KLAKLAK）（2）与从肽文库中选择的癌细胞结合肽（LTVSPWY）或胃泌素释放肽（GNHWAVGHLM）缀合，以将裂解肽导向癌细胞。在乳腺癌 MCF-7 和 MDA-MB-231 癌细胞中测试了肽的细胞毒性。融合肽被癌细胞内化，破坏细胞膜并以低至 4-7 μM 的 IC50 值迅速杀死细胞。肽细胞毒性取决于靶向受体。实际上，添加游离的靶向肽可减少细胞杀伤。血液淋巴细胞和正常的人乳腺上皮细胞对融合肽的敏感性较低。尽管大多数细胞通过坏死被杀死，但与 DNA 寡核苷酸分支的融合肽如通过 Annexin V 染色和 caspase 3 的激活检测到的那样诱导细胞凋亡。因此，新设计的药物肽可能提供一种有效且选择性的抗癌疗法。
