title: Selectively Inducing Cancer Cell Death by Intracellular Enzyme-Instructed Self-Assembly (EISA) of Dipeptide Derivatives.
abstract: Tight ligand-receptor binding, paradoxically, is a major root of drug resistance in cancer chemotherapy. To address this problem, instead of using conventional inhibitors or ligands, this paper focuses on the development of a novel process-enzyme-instructed self-assembly (EISA)-to kill cancer cells selectively. Here it is demonstrated that EISA as an intracellular process to generate nanofibrils of short peptides for selectively inhibiting cancer cell proliferation, including drug resistant ones. As the process that turns the non-self-assembling precursors into the self-assembling peptides upon the catalysis of carboxylesterases (CES), EISA occurs intracellularly to selectively inhibit a range of cancer cells that exhibit relatively high CES activities. More importantly, EISA inhibits drug resistant cancer cells (e.g., triple negative breast cancer cells (HCC1937) and platinum-resistant ovarian cells (SKOV3, A2780cis)). With the IC50values of 28-80 and 25-44 µg mL-1of l- and d-dipeptide precursors against cancer cells, respectively, EISA is innocuous to normal cells. Moreover, using coculture of cancer and normal cells, the selectivity of EISA is validated against cancer cells. Besides revealing that intracellular EISA cause apoptosis or necroptosis to kill the cancer cells, this work illustrates a new approach to amplify the enzymatic difference between cancer and normal cells and to expand the pool of drug candidates for potentially overcoming drug resistance in cancer therapy.
authors.affiliation: Department of Chemistry, Brandeis University, 415 South Street, Waltham, MA, 02454, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Chemistry, Brandeis University, 415 South Street, Waltham, MA, 02454, USA.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Shi
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 Street, Waltham, MA, 02454, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Chemistry, Brandeis University, 415 South Street, Waltham, MA, 02454, USA.
authors.forename: Xuewen
authors.initials: X
authors.lastname: Du
authors.affiliation: Department of Chemistry, Brandeis University, 415 South Street, Waltham, MA, 02454, USA.|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: Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, 300192, China.
authors.forename: Cuihong
authors.initials: C
authors.lastname: Yang
authors.affiliation: Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, 300192, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Liu
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: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Dinulescu
authors.affiliation: Department of Chemistry, Brandeis University, 415 South Street, Waltham, MA, 02454, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Xu
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects*; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism*; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D004151:Dipeptides; D002265:Carboxylic Ester Hydrolases
keywords: anticancer; drug-resistance; enzyme; selectivity; self-assembly