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      Selectively Inducing Cancer Cell Death by Intracellular Enzyme-Instructed Self-Assembly (EISA) of Dipeptide Derivatives

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          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, we focus on the development of a novel process—enzyme-instructed self-assembly (EISA)—to kill cancer cells selectively. Here we demonstrate 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 (TNBC) cells (HCC1937) and platinum-resistant ovarian cells (SKOV3, A2780cis)). With the IC 50 values of 28–80 μg/mL and 25–44 μg/mL of L- and D-dipeptide precursors against cancer cells, respectively, EISA is innocuous to normal cells. Moreover, using co-culture of cancer and normal cells, we validate the selectivity of EISA 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.

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          Contributors
          Journal
          101581613
          40077
          Adv Healthc Mater
          Adv Healthc Mater
          Advanced healthcare materials
          2192-2640
          2192-2659
          3 June 2017
          24 February 2017
          August 2017
          01 August 2018
          : 6
          : 15
          : 10.1002/adhm.201601400
          Affiliations
          Department of Chemistry, Brandeis University, 415 South Street, Waltham, MA 02454, USA
          Department of Chemistry, Brandeis University, 415 South Street, Waltham, MA 02454, USA
          Department of Pathology, Brigham and Women’s hospital, Harvard Medical School, Boston, MA 02115 (USA)
          Department of Chemistry, Brandeis University, 415 South Street, Waltham, MA 02454, USA
          Department of Chemistry, Brandeis University, 415 South Street, Waltham, MA 02454, USA
          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
          Chinese Academy of Medical Science & Peking Union Medical College, Tianjin 300192, China
          Chinese Academy of Medical Science & Peking Union Medical College, Tianjin 300192, China
          State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin, 300071, China
          Department of Pathology, Brigham and Women’s hospital, Harvard Medical School, Boston, MA 02115 (USA)
          Prof. Department of Chemistry, Brandeis University, 415 South Street, Waltham, MA 02454, USA
          Article
          PMC5550337 PMC5550337 5550337 nihpa872859
          10.1002/adhm.201601400
          5550337
          28233466
          76976be6-7b7a-4527-805f-30cfb478e7e0
          History
          Categories
          Article

          enzyme,self-assembly,selectivity,anticancer,drug-resistance
          enzyme, self-assembly, selectivity, anticancer, drug-resistance

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