title: 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.
authors.affiliation: Department of Chemistry, Brandeis University, 415 South St, Waltham, MA 02454 (USA).
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Chemistry, Brandeis University, 415 South St, Waltham, MA 02454 (USA).
authors.forename: Yi
authors.initials: Y
authors.lastname: Kuang
authors.affiliation: Department of Chemistry, Brandeis University, 415 South St, Waltham, MA 02454 (USA).
authors.forename: Junfeng
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Chemistry, Brandeis University, 415 South St, Waltham, MA 02454 (USA).
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 (USA).
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Medina
authors.affiliation: Department of Chemistry, Brandeis University, 415 South St, Waltham, MA 02454 (USA).
authors.forename: Rong
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Department of Chemistry, Brandeis University, 415 South St, Waltham, MA 02454 (USA).
authors.forename: Dan
authors.initials: D
authors.lastname: Yuan
authors.affiliation: Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192 (P.R. China).
authors.forename: Cuihong
authors.initials: C
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin 300071 (China).
authors.forename: Huaimin
authors.initials: H
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin 300071 (China).
authors.forename: Zhimou
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192 (P.R. China).
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 (USA). ddinulescu@rics.bwh.harvard.edu.
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Dinulescu
authors.affiliation: Department of Chemistry, Brandeis University, 415 South St, Waltham, MA 02454 (USA). bxu@brandeis.edu.
authors.forename: Bing
authors.initials: B
authors.lastname: Xu
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D043182:Carboxylesterase / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D015394:Molecular Structure; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D010455:Peptides; D043182:Carboxylesterase; D002945:Cisplatin
keywords: cisplatin; combination therapy; drug-resistance; enzymes; self-assembly