Anti-Tumor Effects of a Penetratin Peptide Targeting Transcription of E2F-1, 2 and 3a Is Enhanced When Used in Combination with Pemetrexed or Cisplatin.
Anti-Tumor Effects of a Penetratin Peptide Targeting Transcription of E2F-1, 2 and 3a Is Enhanced When Used in Combination with Pemetrexed or Cisplatin.
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当与培美曲塞或顺铂联合使用时，靶向E2 F-1、2和3a转录的穿透肽的抗肿瘤作用增强。
DOI：
10.3390/cancers13050972
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发表时间：
2021-02-26
期刊：
影响因子：
5.2
通讯作者：
Bertino JR
中科院分区：
文献类型：
--
作者：
Rather GM;Anyanwu M;Minko T;Garbuzenko O;Szekely Z;Bertino JR
E2F 转录因子家族对于细胞增殖、分化和 DNA 修复至关重要。由于视网膜母细胞瘤蛋白失活或突变，它们在癌症中通常过度表达或失调。因此，一种或多种激活E2F（E2F-1、2和3a）已被认为是抗肿瘤靶点。靶向 E2F-1、2 和 3a 转录的肽与顺铂（尤其是培美曲塞）的组合显示出增强的体外和体内抗肿瘤活性，并有望用于治疗各种肿瘤（特别是肺腺癌）患者。背景：我们测试了修饰的 E2F 肽（用 D-Arg 代替 L-Arg）与渗透素 (PEP) 缀合，单独使用以及与培美曲塞或顺铂联合使用对实体瘤细胞系和 CCRF 白血病细胞系的抗肿瘤作用。对于体内研究，肽被封装在聚乙二醇化脂质体 (PL-PEP) 中以增加半衰期和稳定性。方法：用 D-Arg PEP 联合顺铂或培美曲塞治疗前列腺癌（DU145 和 PC3）、乳腺癌（MCF7、MDA-MB-468 和 4T1）、淋巴瘤（CCRF-CEM）和非小细胞肺癌（NSCLC）细胞系（H2009、H441、H1975 和 H2228）。对 NSCLC 进行 E2F-1、pRb、胸苷酸合酶和胸苷激酶的蛋白质印迹分析。选择H2009细胞系进行体内研究。结果：当PEP与顺铂联合并针对实体瘤细胞系和CCRF-CEM白血病细胞系进行测试时，存在适度的协同作用。当培美曲塞和 PEP 的组合针对腺癌细胞系进行测试时，发现了显着的协同效应。在培美曲塞中添加 PEP 增强了培美曲塞在小鼠 H2009 异种移植物中的抗肿瘤作用。结论：D-Arg PEP 与顺铂联合对前列腺癌、乳腺癌、肺癌和 CCRF-CEM 细胞系产生协同细胞杀伤作用。当 D-Arg PEP 与培美曲塞联合使用来对抗肺腺癌细胞系时，产生了显着的协同作用。一项使用 PL-PEP 与培美曲塞联合使用的异种移植研究显示，与单独使用每种药物相比，抗肿瘤效果增强。
The E2F family of transcription factors are essential for cell proliferation, differentiation, and DNA repair. They are commonly overexpressed or dysregulated in cancer as a consequence of inactivation or mutations in the retinoblastoma protein. Therefore, one or more of the activating E2Fs (E2F-1, 2, and 3a) have been recognized as antitumor targets. The combination of a peptide targeting transcription of E2F-1, 2, and 3a, with cisplatin, and especially with pemetrexed, showed enhanced antitumor activity in-vitro and in-vivo and has promise for the treatment of patients with various tumors, and in particular, lung adenocarcinoma. Background: We tested the antitumor effects of a modified E2F peptide substituting D-Arg for L-Arg, conjugated to penetratin (PEP) against solid tumor cell lines and the CCRF-leukemia cell line, alone and in combination with pemetrexed or with cisplatin. For in-vivo studies, the peptide was encapsulated in PEGylated liposomes (PL-PEP) to increase half-life and stability. Methods: Prostate cancer (DU145 and PC3), breast cancer (MCF7, MDA-MB-468, and 4T1), lymphoma (CCRF-CEM), and non-small cell lung cancer (NSCLC) cell lines (H2009, H441, H1975, and H2228) were treated with D-Arg PEP in combination with cisplatin or pemetrexed. Western blot analysis was performed on the NSCLC for E2F-1, pRb, thymidylate synthase, and thymidine kinase. The H2009 cell line was selected for an in-vivo study. Results: When the PEP was combined with cisplatin and tested against solid tumor cell lines and the CCRF-CEM leukemia cell line, there was a modest synergistic effect. A marked synergistic effect was seen when the combination of pemetrexed and the PEP was tested against the adenocarcinoma lung cancer cell lines. The addition of the PEP to pemetrexed enhanced the antitumor effects of pemetrexed in a xenograft of the H2009 in mice. Conclusions: The D-Arg PEP in combination with cisplatin caused synergistic cell kill against prostate, breast, lung cancers, and the CCRF-CEM cell line. Marked synergy resulted when the D-Arg PEP was used in combination with pemetrexed against the lung adenocarcinoma cell lines. A xenograft study using the PL-PEP in combination with pemetrexed showed enhanced anti-tumor effects compared to each drug alone.
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影响因子：
7.3
作者：
Gorgoulis, VG;Zacharatos, P;Papavassiliou, AG
通讯作者：
Papavassiliou, AG
影响因子：
--
作者：
Shaik, Tazeem;Rather, Gulam M;Bertino, Joseph R
通讯作者：
Bertino, Joseph R
影响因子：
5.3
作者：
Taubert, S;Gorrini, C;Amati, B
通讯作者：
Amati, B
影响因子：
21.1
作者：
Gordon GM;Du W
通讯作者：
Du W
影响因子：
19
作者：
Lammens T;Li J;Leone G;De Veylder L
通讯作者：
De Veylder L