Antiproliferative effect of pHLIP-amanitin.
Antiproliferative effect of pHLIP-amanitin.
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DOI：
10.1021/bi301647y
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发表时间：
2013-02-19
期刊：
影响因子：
2.9
通讯作者：
Reshetnyak YK
中科院分区：
文献类型：
--
作者：
Moshnikova A;Moshnikova V;Andreev OA;Reshetnyak YK
如果能够将毒素选择性地递送到癌细胞中，那么毒素可能是有效的抗癌药物。我们已经表明，pHLIP®（pH低插入肽）家族的水溶性膜肽的膜相关折叠的能量可用于使细胞不可渗透的货物移动穿过癌细胞的细胞质中的脂质双层。在这里，我们提出了一项研究的结果pHLIP介导的细胞传递的极性细胞不可渗透的毒素，α-鹅膏蕈碱，RNA聚合酶II的抑制剂。我们发现pHLIP可以以pH依赖的方式将α-鹅膏蕈碱递送到细胞中，并在48小时内诱导细胞死亡。易位能力可以通过经由在细胞质中可裂解的不同疏水性的接头将鹅膏蕈碱缀合至pHLIP的C-末端来调节。选择pHLIP-SPDP-鹅膏蕈碱作为最佳构建体，pHLIP-SPDP-鹅膏蕈碱在pH 6下表现出比pH 7.4高4-5倍的抗增殖能力。鹅膏蕈碱递送的主要机制是通过pHLIP跨膜直接易位（翻转）和细胞质中S-S键的裂解。在四种不同的人癌细胞系上监测抗增殖作用。pHLIP介导的鹅膏蕈碱的细胞质递送可以为使用该毒素作为有效的pH选择性抗癌剂打开很大的机会，其主要靶向具有低细胞外pH的高度增殖的癌细胞。
Toxins could be effective anti-cancer drugs, if their selective delivery into cancer cells could be achieved. We have shown that the energy of membrane associated-folding of water-soluble membrane peptides of pHLIP® (pH Low Insertion Peptide) family could be used to move cell-impermeable cargoes across the lipid bilayer in cytoplasm of cancer cells. Here we present the results of a study of pHLIP-mediated cellular delivery of a polar cell-impermeable toxin, α-amanitin, inhibitor of RNA polymerase II. We show that pHLIP can deliver α-amanitin into cells in a pH-dependent fashion and induce cell death within 48 hours. Translocation capability could be tuned by conjugating amanitin to the C-terminus of pHLIP via linkers of different hydrophobicity cleavable in cytoplasm. pHLIP-SPDP-amanitin, which exhibits 4–5 times higher anti-proliferative ability at pH 6 compare to pH 7.4, was selected as the best construct. The major mechanism of amanitin delivery is direct translocation (flip) across a membrane by pHLIP and cleavage of S-S bond in a cytoplasm. Anti-proliferative effect was monitored on four different human cancer cell lines. pHLIP-mediated cytoplasmic delivery of amanitin could open great opportunities to use the toxin as a potent pH-selective anti-cancer agent, which predominantly targets highly-proliferative cancer cells with low extracellular pH.
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影响因子：
2.9
作者：
Walton, Jonathan D.;Hallen-Adams, Heather E.;Luo, Hong
通讯作者：
Luo, Hong
影响因子：
10.3
作者：
Moldenhauer, Gerhard;Salnikov, Alexei V.;Faulstich, Heinz
通讯作者：
Faulstich, Heinz
DOI：
10.1073/pnas.0601463103
发表时间：
2006-04-25
影响因子：
11.1
作者：
Reshetnyak, YK;Andreev, OA;Engelman, DM
通讯作者：
Engelman, DM
影响因子：
5.6
作者：
Segala J;Engelman DM;Reshetnyak YK;Andreev OA
通讯作者：
Andreev OA
影响因子：
4.7
作者：
Boomer, Jeremy A.;Qualls, Marquita M.;Inerowicz, H. Dorota;Haynes, Robert H.;Patri, V. Srilakshmi;Kim, Jong-Mok;Thompson, David H.
通讯作者：
Thompson, David H.