Neutrophil Elastase-Activatable Prodrugs Based on an Alkoxyamine Platform to Deliver Alkyl Radicals Cytotoxic to Tumor Cells

Abstract

Current chemotherapies suffer low specificity and sometimes drug resistance. Neutrophil elastase activity in cancer is associated with poor prognosis and metastasis settlement. More generally, tumors harbor various and persistent protease activities unseen in healthy tissues. In an attempt to be more specific, we designed prodrugs that are activatable by neutrophil elastase. Upon activation, these alkoxyamine-based drugs release cytotoxic alkyl radicals that act randomly to prevent drug resistance. As a result, U87 glioblastoma cells displayed high level caspase 3/7 activation during the first hour of exposure in the presence of human neutrophil elastase and the prodrug in vitro. The apoptosis process and cell death occurred between 24 and 48 h after exposure with a half lethal concentration of 150 μM. These prodrugs are versatile and easy to synthetize and can be adapted to many enzymes.

Value of circulating neutrophil elastase for detecting recurrence of differentiated thyroid cancer

“…Neutrophil elastase exerts pro-tumorigenic effects ( 24 ) and promotes dissemination and metastasis of tumor cells ( 25 ). It is involved in awakening cancer cells that are in dormancy, which has been linked to cancer recurrence ( 12 ) and has shown association with prognosis of cancer patients ( 26 ). Cancer cells have the capacity to produce neutrophil elastase ( 27 ) and upregulation of neutrophil elastase has been observed in various types of cancer ( 26 ).…”

“…It is involved in awakening cancer cells that are in dormancy, which has been linked to cancer recurrence ( 12 ) and has shown association with prognosis of cancer patients ( 26 ). Cancer cells have the capacity to produce neutrophil elastase ( 27 ) and upregulation of neutrophil elastase has been observed in various types of cancer ( 26 ). A high level of neutrophil elastase in breast tumor extracts is regarded as an independent indicator of poor prognosis and poor response to tamoxifen therapy ( 28 ).…”

Plasmon-Assisted Chemistry Using Chiral Gold Helicoids: Toward Asymmetric Organic Catalysis

“…A detailed description of the materials used, the preparation of the alkoxyamines and chiral AuNPs, − and the measurement techniques is given in the Supporting Information.…”

Conditional generation of free radicals by selective activation of alkoxyamines: towards more effective and less toxic targeting of brain tumors

“…5 More recently, Seren S. et al reported a new series of alkoxyamines, based on phenol or aniline cores, that also inhibited U87-MG cell survival but with IC 50 values 25 times higher than ALK4 in the same cell model. 16 To further investigate ALK4, ALK5, ALK9 and ALK13 anticancer properties, a Transwell assay was carried out. It showed that the alkoxyamines were also effective in inhibiting GBM cell migration at low doses (Fig.…”