A novel lytic peptide composed of DL-Amino acids selectively kills cancer cells in culture and in mice
A novel lytic peptide composed of DL-Amino acids selectively kills cancer cells in culture and in mice
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DOI：
10.1074/jbc.m211204200
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发表时间：
2003-06-06
影响因子：
4.8
通讯作者：
Shai, Y
中科院分区：
文献类型：
--
作者：
Papo, N;Shahar, M;Shai, Y
大多数化疗药物的高毒性和多药耐药表型的失活促使人们广泛寻找具有新作用模式的药物。我们设计了一种由D-和L-亮氨酸、赖氨酸和精氨酸组成的阳离子非对映异构体短肽，对癌细胞具有选择性毒性，并显著抑制小鼠肺转移形成(86%)，且没有检测到副作用。它能够以相同的速度(几分钟内)和相同的浓度(3微米)使癌细胞的跨膜电位去极化，从而显示出生物活性，这表明了一种涉及质膜扰动的杀伤机制。共聚焦显微镜实验证实，细胞死于急性损伤、肿胀和破裂，表明是坏死。生物传感器结合实验和衰减全反射傅里叶变换红外光谱模型膜实验证明了其对癌细胞的高选择性。虽然这是一项初步的研究，着眼于肿瘤形成而不是多肽减少已建立的肿瘤的能力，但多肽的简单序列、高溶解性、对降解的显著抵抗力以及血清成分的失活可能使其成为未来抗癌治疗的良好候选者。
The high toxicity of most chemotherapeutic drugs and their inactivation by multidrug resistance phenotypes motivated extensive search for drugs with new modes of action. We designed a short cationic diastereomeric peptide composed of D- and L-leucines, lysines, and arginines that has selective toxicity toward cancer cells and significantly inhibits lung metastasis formation in mice (86%) with no detectable side effects. Its ability to depolarize the transmembrane potential of cancer cells at the same rate (within minutes) and concentration (3 muM), at which it shows biological activity, suggests a killing mechanism that involves plasma membrane perturbation. Confocal microscopy experiments verified that the cells died as a result of acute injury, swelling, and bursting, suggesting necrosis. Biosensor binding experiments and attenuated total reflectance-Fourier transform infrared spectroscopy using model membranes have substantiated its high selectivity toward cancer cells. Although this is an initial study that looked at tumor formation rather than the ability of the peptides to reduce established tumors, the simple sequence of the peptide, its high solubility, substantial resistance to degradation, and inactivation by serum components might make it a good candidate for future anticancer treatment.