Enzymatic Self-Assembly Confers Exceptionally Strong Synergism with NF-κB Targeting for Selective Necroptosis of Cancer Cells

• DOI: 10.1021/jacs.7b12368
• Publication Date: 2018-01-29T21:57:33Z
• Authors: Jie Zhou; Xuewen Du; Xiaoyi Chen; Jiaqing Wang; Ning Zhou; Difei Wu; Bing Xu
• Keywords: Cell Survival; NF-kappa B; Nanofibers; Antineoplastic Agents; Apoptosis; 01 natural sciences; 0104 chemical sciences; 3. Good health; Cell Line, Tumor; Neoplasms; Biocatalysis; Humans; Receptors, Tumor Necrosis Factor, Type II; Molecular Targeted Therapy; Oligopeptides; Signal Transduction

As a promising molecular process for selectively inhibiting cancer cells without inducing acquired drug resistance, enzyme-instructed self-assembly (EISA) usually requires relatively high dosages. Despite its discovery 30 years ago, the translation of knowledge about NF-κB signaling into clinic remains complicated due to broad roles in cellular regulation. Here we show that integrating EISA and targeting boosts efficacy over an order magnitude compromising selectivity against cells. That is, situ enzymatic tetrapeptide results nanofibers, which hardly affect cell viability, but lead inductive expression tumor necrosis factor receptor 2 (TNFR2) decreased three key proteins at upstream pathway Adding inhibitors further decreases expressions those proteins, turns otherwise innocuous nanofibers being lethal cells, likely causing necroptosis. first case using supramolecular processes enable synthetic lethality, this work illustrates versatile approach translate regulatory circuits therapeutic targets.