Modeling and antitumor studies of a modified L-penetratin peptide targeting E2F in lung cancer and prostate cancer.
Modeling and antitumor studies of a modified L-penetratin peptide targeting E2F in lung cancer and prostate cancer.
复制标题
DOI：
10.18632/oncotarget.26064
复制
发表时间：
2018-09-07
期刊：
影响因子：
--
通讯作者：
Bertino, Joseph R
中科院分区：
文献类型：
--
作者：
Shaik, Tazeem;Rather, Gulam M;Bertino, Joseph R
由于成视网膜细胞瘤基因的扩增或突变或缺失导致的E2 F1 -3a过表达诱导参与DNA合成的基因并导致异常细胞增殖、肿瘤生长和侵袭。因此，抑制这些活化E2 F中的一种或多种的过表达是癌症治疗中公认的靶标。在以前的研究中，我们确定了噬菌体展示，一种新的7-mer肽（PEP），紧密结合到一个固定的共识E2 F1启动子序列，并结合到penetratin，以增加其进入细胞的摄取，是细胞毒性的几种恶性细胞系和人前列腺和小细胞肺癌异种移植。基于分子模拟研究表明D-Arg穿透肽（D-Arg PEP）的二级结构比L-Arg PEP更稳定，将肽中的L-Arg替换为D-Arg。体外研究证实，当针对人去势抵抗细胞系DU 145和人肺癌H196细胞系进行测试时，其比L-型更稳定，并且与L-Arg PEP相比更具细胞毒性。当包封在PEG化脂质体中时，D-Arg-PEP有效地抑制小鼠中DU 145异种移植物的生长。我们的研究结果验证了D-Arg PEP，一种E2 F1和3a转录的抑制剂，作为一种改进的第二代候选药物，用于具有升高的活化E2 F水平的癌症的靶向分子治疗。
E2F1-3a overexpression due to amplification or to mutation or loss of the retinoblastoma gene, induces genes involved in DNA synthesis and leads to abnormal cellular proliferation, tumor growth, and invasion. Therefore, inhibiting the overexpression of one or more of these activating E2Fs is a recognized target in cancer therapeutics. In previous studies we identified by phage display, a novel 7-mer peptide (PEP) that bound tightly to an immobilized consensus E2F1 promoter sequence, and when conjugated to penetratin to increase its uptake into cells, was cytotoxic to several malignant cell lines and human prostate and small cell lung cancer xenografts. Based on molecular simulation studies that showed that the D-Arg penetratin peptide (D-Arg PEP) secondary structure is more stable than the L-Arg PEP, the L-Arg in the peptide was substituted with D-Arg. In vitro studies confirmed that it was more stable than the L- form and was more cytotoxic as compared to the L-Arg PEP when tested against the human castrate resistant cell line, DU145 and the human lung cancer H196 cell line. When encapsulated in PEGylated liposomes, the D-Arg-PEP potently inhibited growth of the DU145 xenograft in mice. Our findings validate D- Arg PEP, an inhibitor of E2F1and 3a transcription, as an improved second generation drug candidate for targeted molecular therapy of cancers with elevated levels of activated E2F(s).