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Enzyme-Instructed Intracellular Molecular Self-Assembly to Boost Activity of Cisplatin against Drug-Resistant Ovarian Cancer Cells.

Abstract
Anticancer drug resistance demands innovative approaches that boost the activity of drugs against drug-resistant cancers without increasing the systemic toxicity. Here we show the use of enzyme-instructed self-assembly (EISA) to generate intracellular supramolecular assemblies that drastically boost the activity of cisplatin against drug-resistant ovarian cancer cells. We design and synthesize small peptide precursors as the substrates of carboxylesterase (CES). CES cleaves the ester bond pre-installed on the precursors to form the peptides that self-assemble in water to form nanofibers. At the optimal concentrations, the precursors themselves are innocuous to cells, but they double or triple the activity of cisplatin against the drug-resistant ovarian cancer cells. This work illustrates a simple, yet fundamental, new way to introduce non-cytotoxic components into combination therapies with cisplatin without increasing the systemic burden or side effects.
AuthorsJie Li, Yi Kuang, Junfeng Shi, Jie Zhou, Jamie E Medina, Rong Zhou, Dan Yuan, Cuihong Yang, Huaimin Wang, Zhimou Yang, Jianfeng Liu, Daniela M Dinulescu, Bing Xu
JournalAngewandte Chemie (International ed. in English) (Angew Chem Int Ed Engl) Vol. 54 Issue 45 Pg. 13307-11 (Nov 02 2015) ISSN: 1521-3773 [Electronic] Germany
PMID26365295 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Copyright© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Chemical References
  • Antineoplastic Agents
  • Peptides
  • Carboxylesterase
  • Cisplatin
Topics
  • Antineoplastic Agents (chemistry, pharmacology)
  • Carboxylesterase (metabolism)
  • Cell Line, Tumor
  • Cell Survival (drug effects)
  • Cisplatin (chemistry, pharmacology)
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm (drug effects)
  • Female
  • Humans
  • Molecular Structure
  • Ovarian Neoplasms (drug therapy, pathology)
  • Peptides (chemistry, metabolism)
  • Structure-Activity Relationship

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