期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 167, 期 -, 页码 377-387出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2019.02.041
关键词
NSAID-Pt(IV) prodrug; Antitumor; Metastasis and invasion; COX-2; Synergistic effect
资金
- National Natural Science Foundation of China [21371135]
- Tianjin Municipal Natural Science Foundation [17JCZDJC33100, 13JCZDJC28200]
- Science & Technology Development Fund of Tianjin Education Commission for Higher Education [2016YD17]
- Postgraduate Innovation Fund of '13th Five-Year comprehensive investment' of Tianjin Medical University [YJSCX201818]
The great interest in epithelial-to-mesenchymal transition (EMT) programme lies in its association with process of metastasis and invasion, which is a crucial cause of cancer-related death. Herein, we designed and reported three new NSAID-Pt(IV) prodrugs, taking Non-Steroid Anti-Inflammatory Drugs (NSAIDs) to disrupt EMT programme and assist genotoxic platinum-based drugs as a cytotoxicity booster, to offer a class of potential anticarcinogens with a multi-functional action mechanism. The NSAID-Pt(IV) prodrugs, especially Eto-Pt(IV), highly enhanced cellular uptake with amount up to 42-fold at 3 h compared with CDDP, and greatly increased DNA damage and cell apoptosis, showing much higher cytotoxicity than cisplatin in the tested cancer cells even in A549/cis cells. Among of them, Eto-Pt(IV) and Car-Pt(IV) exhibited more excellent activity than Sul-Pt(IV), arising from their reduction-labile and favorable lip-ophilicity. Most strikingly, Eto-Pt(IV) markedly inhibited metastasis and invasion of MCF-7 cells, owing to its COX-2 suppression that down-regulated active MMP-2, vimentin protein and up-regulated E-cadherin. In vivo, Eto-Pt(IV) displayed potent antitumor activity and no observable toxicity in BALB/c nude mice bearing MCF-7 tumors. (C) 2019 Elsevier Masson SAS. All rights reserved.
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