Small lytic peptides escape the inhibitory effect of heparan sulfate on the surface of cancer cells.
Small lytic peptides escape the inhibitory effect of heparan sulfate on the surface of cancer cells.
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DOI：
10.1186/1471-2407-11-116
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发表时间：
2011-03-31
期刊：
影响因子：
3.8
通讯作者：
Rekdal Ø
中科院分区：
文献类型：
--
作者：
Fadnes B;Uhlin-Hansen L;Lindin I;Rekdal Ø
几种天然存在的阳离子抗菌肽（CAP），包括牛乳铁蛋白（LfcinB），显示出有前途的抗癌活性。这些肽不受多药耐药机制的影响，并已显示出诱导针对实体瘤的保护性免疫应答，从而使它们成为开发用于抗癌治疗的新型先导结构的有趣候选物。最近，我们发现LfcinB的抗癌活性被肿瘤细胞表面硫酸乙酰肝素（HS）的存在所抑制。基于对LfcinB进行的广泛的结构-活性关系研究，已经构建了更短、更有效的肽。在本研究中，我们研究了三种化学修饰的9-mer肽的抗癌活性以及HS和硫酸软骨素（CS）对其细胞毒活性的影响。使用各种细胞系和红细胞来研究肽的抗癌活性和选择性。通过使用比色MTT活力测定来测量肽对不同细胞系的细胞毒性作用。利用HS/CS表达细胞系和HS/CS缺陷细胞系评价HS和CS对其细胞毒活性的影响。还研究了可溶性HS和CS抑制肽的细胞毒活性的能力以及肽对HS和CS的亲和力。9-mer肽显示出选择性的抗癌活性。表达HS/CS的细胞与不表达HS/CS的细胞相比对肽同样敏感或更敏感。与CS相比，肽显示出对HS更高的亲和力，并且外源添加的HS抑制肽的细胞毒性作用。与先前报道的HS对LfcinB的抑制作用相反，本研究表明，小裂解肽的细胞毒性活性增加或不受细胞表面HS的影响。
Several naturally occurring cationic antimicrobial peptides (CAPs), including bovine lactoferricin (LfcinB), display promising anticancer activities. These peptides are unaffected by multidrug resistance mechanisms and have been shown to induce a protective immune response against solid tumors, thus making them interesting candidates for developing novel lead structures for anticancer treatment. Recently, we showed that the anticancer activity by LfcinB was inhibited by the presence of heparan sulfate (HS) on the surface of tumor cells. Based on extensive structure-activity relationship studies performed on LfcinB, shorter and more potent peptides have been constructed. In the present study, we have investigated the anticancer activity of three chemically modified 9-mer peptides and the influence of HS and chondroitin sulfate (CS) on their cytotoxic activity. Various cell lines and red blood cells were used to investigate the anticancer activity and selectivity of the peptides. The cytotoxic effect of the peptides against the different cell lines was measured by use of a colorimetric MTT viability assay. The influence of HS and CS on their cytotoxic activity was evaluated by using HS/CS expressing and HS/CS deficient cell lines. The ability of soluble HS and CS to inhibit the cytotoxic activity of the peptides and the peptides' affinity for HS and CS were also investigated. The 9-mer peptides displayed selective anticancer activity. Cells expressing HS/CS were equally or more susceptible to the peptides than cells not expressing HS/CS. The peptides displayed a higher affinity for HS compared to CS, and exogenously added HS inhibited the cytotoxic effect of the peptides. In contrast to the previously reported inhibitory effect of HS on LfcinB, the present study shows that the cytotoxic activity of small lytic peptides was increased or not affected by cell surface HS.
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DOI：
10.1073/pnas.82.10.3197
发表时间：
1985-01-01
影响因子：
11.1
作者：
ESKO, JD;STEWART, TE;TAYLOR, WH
通讯作者：
TAYLOR, WH
影响因子：
5.8
作者：
Berge, Gerd;Eliassen, Liv Tone;Rekdal, Oystein
通讯作者：
Rekdal, Oystein
影响因子：
12.3
作者：
Filmus J;Capurro M;Rast J
通讯作者：
Rast J
影响因子：
4.8
作者：
Bai, XM;Wei, G;Esko, JD
通讯作者：
Esko, JD
影响因子：
15.9
作者：
Kleeff, J;Ishiwata, T;Korc, M
通讯作者：
Korc, M